bypassing p-glycoprotein drug efflux mechanisms: possible ... · extended phenotype: general...

Review ArticleBypassing P-Glycoprotein Drug Efflux Mechanisms PossibleApplications in Pharmacoresistant Schizophrenia Therapy

Famida G Hoosain Yahya E Choonara Lomas K Tomar Pradeep Kumar Charu TyagiLisa C du Toit and Viness Pillay

Wits Advanced Drug Delivery Platform Research Unit Department of Pharmacy and Pharmacology School of Therapeutic SciencesFaculty of Health Sciences University of the Witwatersrand 7 York Road Parktown Johannesburg 2193 South Africa

Correspondence should be addressed to Viness Pillay vinesspillaywitsacza

Received 2 December 2014 Revised 8 May 2015 Accepted 10 May 2015

Academic Editor Eberval G Figueiredo

Copyright copy 2015 Famida G Hoosain et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

The efficient noninvasive treatment of neurodegenerative disorders is often constrained by reduced permeation of therapeuticagents into the central nervous system (CNS) A vast majority of bioactive agents do not readily permeate into the brain tissuedue to the existence of the blood-brain barrier (BBB) and the associated P-glycoprotein efflux transporter The overexpression oftheMDR1 P-glycoprotein has been related to the occurrence ofmultidrug resistance in CNS diseases Various research outputs havefocused on overcoming the P-glycoprotein drug efflux transporter which mainly involve its inhibition or bypassing mechanismsStudies into neurodegenerative disorders have shown that the P-glycoprotein efflux transporter plays a vital role in the progressionof schizophrenia with a noted increase in P-glycoprotein function among schizophrenic patients thereby reducing therapeuticoutcomes In this review we address the hypothesis that methods employed in overcoming P-glycoprotein in cancer and otherdisease states at the level of the BBB and intestine may be applied to schizophrenia drug delivery system design to improve clinicalefficiency of drug therapies In addition the current review explores polymers and drug delivery systems capable of P-gp inhibitionand modulation

1 Introduction

The effectiveness of drug treatments for numerous diseasestates such as cancer infectious diseases and central nervoussystem (CNS) disorders (epilepsy depression and schizo-phrenia) is limited by poor therapeutic outcomes or drugresistance The outcomes of drug treatment can be viewed asan interchange of several gene products that have an effecton pharmacokinetics and pharmacodynamics These geneproducts mainly include metabolizing enzymes and drugtransporters and alterationswithin any of these gene productsmay lead to a reduction in clinical outcomes [1] In particularthe clinical treatment and management of CNS disordersnecessitate that a sufficient amount of drug must enter thebrain The use of oral drug delivery systems is beneficial inthe treatment of neurodegenerative disorders as complianceto therapy becomes challenging [2] However an imperativefactor determining the entry of drugmolecules into the brain

via oral administration is its absorption through the intestinalepithelium and the permeability of the blood-brain barrier(BBB) Passive diffusion across the intestinal epithelium isdependent on many physiochemical characteristics of drugssuch as lipophilicity molecular weight and hydrophobicbonding [3] The same principle applies to passive diffusionacross the BBB although passive diffusion across the BBBis limited to small lipophilic molecules Active efflux of thedrug into the intestine and from BBB endothelium back intothe blood are the most important mechanisms underlyingreduced brain uptake of active drug molecules post oraldosing [4]

The development of drug delivery systems involved inthe treatment of neurodegenerative disorders requires a vitalconsideration of achievable brain concentrations Factors thatimpact the brain uptake and concentrations of drugs include(i) the extent of intestinal absorption after oral administra-tion (ii) the rate and extent of transport across the BBB

Hindawi Publishing CorporationBioMed Research InternationalVolume 2015 Article ID 484963 21 pageshttpdxdoiorg1011552015484963

2 BioMed Research International

into the brain (iii) metabolic stability of the drug and(iv) the active transport out of the intestine and brainendothelium via efflux pump transporters There are threeclasses of transporters that have been associated with theefflux of drugs-monocarboxylic acid transporters organicion transporters and multidrug resistance transporters Thisremarkable system of transporters provides a viable mecha-nism through which the permeation of CNS targeted drugsinto the brain is effectually decreased The action of theseefflux transporters at the level of the intestine and BBBmay bedemonstrated clinically as the reduced effectiveness of drugtherapy targeted at CNS disorders [5]

In addition various multispecific transport proteins havealso been identified within the intestine and BBB Some ofthese belong to the ATP-binding cassette (ABC) superfamilyof transporters with P-glycoprotein (P-gp) multidrug resis-tance associated protein (MRP) and breast cancer resistanceprotein (BCRP) as representative examples [4 6] P-gp isa membrane transporter of the ABC superfamily locatedwithin both the intestinal epithelium and the BBB thusplaying a dynamic role in the bioavailability of orally adminis-tered drugs employed in the treatment of neurodegenerativedisorders [7] We propose that drug molecules intended forthe treatment of CNS disorders must be capable of bypassingthe P-gp efflux pump at the intestinal and BBB levels so as toattain effective brain concentrations

Regardless of the vast advances in brain research out-puts neurodegenerative and psychiatric disorders remain theworldrsquos leading causes of disability morbidity and mortality[8] Dysfunctions in the P-gp efflux transporter have alreadybeen suggested to play a role in the development of neu-rodegenerative disorders such as Parkinsonrsquos andAlzheimerrsquosdiseases Genetic variations in theMDR1 gene associatedwithreduced P-gp function at the BBB have been related to ahigher risk of Parkinsonrsquos diseaseThe reduced function of theP-gp efflux pump has been noted in most neurodegenerativedisorders It has been hypothesized that the decreased P-gpfunction in the BBBmay increase the risk and hence the inci-dence of neurological diseases [9] In schizophrenia geneticvariations of the ABCB1 (ATP-binding cassette subfamilyB) gene also known as the MDR1 (multidrug resistance)gene have been described as the predisposing factors forschizophrenia and other neurodegenerative diseases Theyhave also been employed as determinants of treatmentresponse to antipsychotics [10] As in other neurodegener-ative diseases the BBB maybe compromised by way of theinflammatory and neurodegenerative processes [11] hencethe functionality of P-gp is influenced by the inflammatoryresponses [12] As discussed previously there exists a reduc-tion of P-gp function in progression of neurodegenerativediseases Conversely there is evidence of increased P-gpfunction in patients presenting with schizophrenia [13]

Schizophrenia is a neurodegenerative disorder that isknown to affect approximately 1 of the worldrsquos population[14] with a further 25 of patients approximated to beafflicted by the disease experiencing nonremitting sickness[15] The disorder is characterized by disturbances of per-ception thought and volition with significant impairmentin social and occupational functioning Studies have shown

that roughly 10 of schizophrenic patients commit suicideA recent study showed that more than 70 of patientsdiagnosed with chronic schizophrenia discontinued theirantipsychotic drug therapy due to poor effectiveness ortolerability [16ndash22]

Schizophrenia is clinically characterized by the incidenceof symptoms such as hallucinations and delusions which arecollectively termed ldquopositiverdquo symptoms whereas symptomspertaining to expression of emotional dullness and socialwithdrawal are recognized as ldquonegativerdquo symptoms [15]Figure 1(a) diagrammatically depicts the symptom cascade

Schizophrenia is widely characterized via a successivecourse that involves three distinct phases namely phase1 (premorbid) defined by cognitive motor and societaldysfunction phase 2 (prodromal) which is characterized byweakened positive symptoms and accompanying deteriorat-ing functionality and phase 3 (plateau) in which the positivepsychosis defining symptoms are less conspicuous and thenegative symptoms including cognitive deficits are generallypredominant [23] Figure 1(b) illustrates the clinical stages ofschizophrenia progression

It has been discovered that ldquopharmacoresistant schizo-phreniardquo is a noteworthy obstacle to the successful manage-ment of the disease within the clinical settingThe prevalenceof pharmacoresistant schizophrenia is understood to beapproximately 129 to 48 of all schizophrenic patients andpersists regardless of the use of drug combination treatmentregimens with possible therapeutic efficacy Majority ofpatients presenting with treatment resistant schizophreniaare on atypical antipsychoticmedication Recent in vitro stud-ies have shown that drugs such as amisulpride risperidonequetiapine and clozapine have a varying degree of affinityfor the P-gp efflux transporter [24ndash26] An additional studywas conducted to determine the effect that cyclosporine Aa P-gp inhibitor has on the brain uptake of amisulpride (arecognized P-gp substrate) In vitro and in vivo results dis-played that amisulpride when coadministered with 50mgkgof cyclosporine A showed an increase and prolonged antipsy-chotic effect The area under the curve (AUC) in serum andthe brain was increased in cyclosporine cotreated rats Thesedata points indicated a pharmacokinetic interaction betweencyclosporine A and amisulpride which is most likely dueto P-gp inhibition [27] Thus the expression and functionof the P-gp efflux transporter have been recently impli-cated in the occurrence of pharmacoresistant schizophreniaAntipsychotic drugs have also been shown to stimulate thecatalytic activity of P-gp providing additional evidence ofthe participation of P-gp-mediated drug extrusion processesin restraining CNS penetration of these drugs It has beensuggested that some of the principles observed with thecombination treatment of P-gp-mediated drug resistance incancer may be applied to elucidate the involvement of P-gp indrug-resistant schizophrenia There exists a greatly emergentbody of evidence supporting the role of P-gp on the effluxof antipsychotic agents from the BBB however limitedconsideration has been focused on the modulation of P-gpfunction by polymeric materials excipients and drug deliv-ery systems used in other P-gpmodulated treatment-resistantdisease states [24]

BioMed Research International 3

Extended phenotype general population

Clinical phenotype psychiatric services

gtEnvironmentalimpact

gtDevelopmentalimpairment

gtMengtWomen

Behavioural expressionvulnerability 10ndash20

Sever

itySeverity

Affective

Psychosis Negative

Cognitive

Heritability

HeritabilityHeritability

HeritabilityHeritabilitysim40

sim40 sim40

sim40ndash70

sim80ndash90

Disorder prevalence 3Mental

health

care fi

lter

Mental health

care filterHelp

seekingReduced social

Socialconflict

competence

G times E

(a)

(i) Loss offunctionalityfurther medicaldifficulties

(ii) Unemploymentandhomelessnessrife

Stage 4

(i) Atypicalthought andbehavior

(ii) Possiblerelapse

(iii) Loss offunctionalityand insight

Stage 3

(i) Socialbehavioralandcognitivedeficits

pursuing

Stage 2

(i) Geneticpredispositionorenvironmentalexposure

(ii) Family history(iii) Mild cognitive

dysfunction

Stage 1

(ii) Help

(b)

Figure 1 (a) Description of the aetiological complexity of schizophrenia [14] (reproduced with permission from Macmillan Publishers LtdNature 2010) (b) Stages of schizophrenia progression [23] (reproduced with permission from Elsevier BV Ltd copy 2009)

This review will provide a brief overview of the effluxtransporters associated with the intestine and BBB followedby P-gp efflux transporterrsquos mechanism of action its role inCNS drug delivery and current and potential schizophreniatherapy Additionally the review will provide a discussion onpharmaceutical excipients and novel drug delivery systemsemployed in other CNS related disease states that have a pos-sible future application in schizophrenia due to P-gp modu-lation or inhibition

2 Structure and Function of the Intestine andP-gp Intestinal Expression in Drug Delivery

The absorption of drugs via the oral route is always underexamination due to the fact that good bioavailability indicates

that the drug is able to reach systemic circulation Oral drugabsorption is affected by both drug properties and the phys-iology of the gastrointestinal tract (GIT) [28] Oral bioavail-ability is a collective outcome of fraction absorbed fractionescaping gut-wall elimination and the fraction avoidinghepatic elimination The factors that affect the bioavailabilityare divided into physiological physiochemical and biophar-maceutical factors [29] The sequence of actions determiningthe systemic availability of drug molecules subsequent totheir oral administration is well acknowledged However forparticular drugs the process leading to drug absorption andbioavailability is complex Certain mechanisms may involvepoor drug solubility poor permeability degradation (enzy-maticnonenzymatic) and first pass hepatic metabolism [3]Following oral dosing drug molecules cross the luminal


membrane via a diversity of mechanisms that comprise ofpassive diffusion or active transport Passive diffusion isdivided into two pathways the paracellular and transcellularpathway in which the paracellular pathway drug moleculesare absorbed via diffusion and convection volume flowthrough the water filled intercellular space [29]

The active transport pathway is mediated by transportersand is divided into influx and efflux The applicability of thevarious routes is determined by the compounds physiochem-ical properties and their relative affinity for various transportproteins Enterocytes express several transporters belongingto the Adenosine triphosphate (ATP) binding cassette (ABC)superfamily and solute carrier (SC) super families on the api-cal and basolateral surface ofmembranes with the function ofinflux and efflux of endogenous substances A wide diversityof transporters are expressed in enterocytes however only aselect few have been implicated in the intestinal absorption ofdrugs ABC transporters utilize ATP to power the transportand are thus called primary active transporters Solute carrier(SLC) transporters employ ion gradients (H+ Na+ andCa++)across the membrane by active carriers ABC transportersthat are expressed in the intestine include P-glycoprotein (P-gp) breast cancer resistant protein (BCRP) and multidrugresistance protein (MRP) which are localized on the brushborder membrane of enterocytes Efflux transporters mech-anistically limit the enterocytic levels of their respective sub-strates by reducing uptake and facilitating effluxwhereas SLCtransporters which include peptide transporter (PepTI) andorganic anion polypeptide transporter (OATP1A2) amongstothers are secondary active transporters that employ energycoupling mechanisms [29 30]

During oral absorption in addition to the physical pro-cesses mentioned above (solubility permeability etc) P-gp-mediated efflux across the apical membrane has an effecton the rate and concentration of drug diffusing across thebasolateral membrane and thus entering general circulationfrom the intestine It has been estimated that 50ndash60 of newand 40ndash50 of existing drugs molecules are lipophilic innature and more than 25 of these agents are known P-gpsubstrates [2] Pumps in the intestinal epithelium transportsubstrates from the intestinal lumen to the general bloodcirculation [31] P-gp identifies with a diversity of structurallyand pharmacologically dissimilar hydrophobic substancesThe P-gp efflux pump transporter restricts the influx into andfacilitates efflux from enterocytes of its substrates Thereforethe P-gp efflux transporter is recognized as a determiningfactor of oral bioavailability and intestinal efflux of drugs[3] In the human intestine P-gp is highly expressed onthe apical surface of superficial columnar epithelial cells ofthe colon and ileum (Figure 2) while expression decreasesproximally into the jejunum duodenum and stomach [3]Since the oral route of drug administration is the mostpreferred as previously mentioned it is vital to overcomethe absorption barrier posed by the P-gp efflux transporter[2] Additionally as discussed earlier P-gp plays a role inrestricting cellular uptake of drugs from the general bloodcirculation into the brain due to its presence within the BBBas well Research outputs have shown that intestinal P-gp canbe inhibited by various compounds resulting to an increasein oral absorption of P-gp substrate drugs [3]

P-gp

MRP2

MRP1

MRP3

MRP4

MRP5

MCT1

OCT1

OCT2

BloodEnterocyte

Apical

Intestinallumen

Junctionalcomplex

Basolateral

OATPs

BCRP

PEPTOCTNs

PMAT

Figure 2 Drug Efflux by P-glycoprotein in the intestine [115](reproduced with permission from Elsevier BV Ltd copy 2013)

Physiological factors that influence oral drug absorptionare absorption rate of a drug which is a function of drugabsorption via the GIT and gastro intestinal transit timewhich influences the systemic exposure of rapidly dissolvedand highly absorbed drugs Intestinal transit time impactsthe absorption of drugs with limited mucosal permeabilityand carrier-mediated uptake and drugs that are subjected tointestinal degradation In addition the degree of ionizationplays a key role in determining drug dissolution rate andthe passive permeability across the GIT The pH at theabsorption site is also a vital factor in allowing or inhibitingthe dissolution and absorption of many ionizable drugs [29]

In addition there are biopharmaceutical factors thatinfluence oral drug absorption amongst these is the salt formof a drug molecule which changes the coulombic attractionbetween the drug molecule and its respective counter ionthus altering the potential energy when in a solid stateThis is usually associated with an alteration of the pH ofthe diffusion layer at the surface of the dissolving solidthereby greatly increasing the solubility of the drugmoleculeThe amorphous form alternatively tends to improve thedissolution rate and solubility significantly compared to itscrystalline form which increases the rate and degree of oralabsorption [29] Apart from these mechanisms the smallintestine has the ability to metabolize drugs via a diversity ofpathways involving phase I and phase II reactions which inturn may cause a restriction in oral bioavailability CYP3A4is the most abundant cytochrome P450 enzyme within theintestinal enterocytes that is implicated in the metabolicelimination of many drugs [29]

3 Structure and Function of the BBB and P-gpExpression in Drug Delivery

The BBB is a specialized system of capillary endothelial cellsas shown in Figure 3 which assists in protecting the brainfrom harmful substances within the blood stream while sup-plying the brain with nutrients that are necessary for properfunction The BBB has many functions including mainte-nance of the internal environment of the brain protection


Lumen of blood vessel

Astrocyte

Basement membrane

Neuron Tight junction

Pericyte

Endothelial cell

Blood

Lymphocyte

Monocyte

Neutrophil

Blood-brainbarrier

Brain Microglia

Astrocyte

Tight junction

Endothelial cell

Basementmembrane

Figure 3 Schematic representation of the cross section of the BBB cerebral capillary [116] (reproduced with permission from Elsevier BVLtd copy 2007)

of the brain from fluctuations in ionic composition anddrainage of cerebrospinal fluid and interstitial fluid Due to itsprotective function the BBB restricts transport of substancesinto the brain via both the physical (tight junctions) and themetabolic (enzyme) barriers [32 33]

The BBB is composed of a monolayer of brain capillaryendothelial cells The limitation of drug uptake by the BBBarises via the presence of tight junctions between adjacentcapillary endothelial cells and the relative lack of fenestraeas well as pinocytotic vesicles within the endothelial cellmonolayer In turn brain capillary endothelial cells are sur-rounded by an extracellular matrix pericytes and astrocytefoot processes Once a drug molecule enters the brain eithervia transport across the BBB after systemic administrationor by direct administration into the CNS the drug mayreturn to the blood via three ways (1) It may pass throughthe capillary endothelial cells of the brain (2) cross theepithelial cells of the choroid plexus (3) or return to systemiccirculation by bulk flow of cerebrospinal fluid that effectivelyresults in reabsorption at the arachnoid villi [5] The BBB isknown to express a high degree of active efflux transporter

proteins including as mentioned previously P-gp MRP-1and BCRP Lipophilic molecules of approximately 500ndash600Daltonsmay diffuse passively into theCNSHowever the vastmajority of molecules of a molecular weight greater than 600Daltons do not cross the BBB (Figure 4) Therefore in orderto reach the brain most drug molecules must cross the BBBvia an interaction with specific transporters occurring at theluminal surface of the endothelial cells [1 34ndash36]

The pharmacodynamics and pharmacokinetics of CNStargeted drugs are determined by their unbound concen-trations in the extracellular fluid of the brain Several invivo and in vitro procedures are accessible to study theseproperties The efflux transport across the BBB is an imper-ative process utilized in the explanation of the mechanismof the apparent restricted cerebral distribution of drugsafter their systemic administration To examine the BBBefflux transport mechanism under in vivo conditions anintracerebral microinjection technique has been developedand newly estimated as the BEI (Brain Efflux Index) BEI isdefined as the relative percentage of drug that is effluxed fromthe ipsilateral (does not cross the opposite hemisphere of the


Table 1 The net uptake of bioactive by the brain depends on the difference between the influx and efflux processes [38] (reproduced withpermission from Elsevier BV Ltd copy 2002)

Blood lumen Endothelial cell Extracellular fluid(i) Blood Systemic exposure Influx clearance

997888997888997888997888997888997888997888997888997888997888997888997888997888997888997888rarr

(ii) Drug blood cell and protein binding (i) Drug permeability(ii) Drug metabolism Drug disposition

Efflux clearancelarr997888997888997888997888997888997888997888997888997888997888997888997888997888997888997888

MRP1

MRP2

MRP3

MRP4

MRP6MRP5

P-gp BCRP

Apicalluminal

Basolateral

Blood

Brain

Brain capillary endothelial cell

Tightjunction

Figure 4 Respective locations of the drug efflux proteins on brain capillary endothelial cells that collectively form the BBB [35] (reproducedwith permission from Elsevier BV Ltd copy 2005)

brain) cerebrum to the circulating blood as compared withthe amount of drug injected into the cerebrum as shown

BEI =Amount of drug effluxed at the BBBAmount of drug injected into the BBB

times 100 (1)

However limitations of the BEImethod are that only one datapoint may be obtained for a single intracerebral injectionand the concentration the drug in the cerebrum cannot beaccurately determined [37]

The net uptake of a drug molecule by the brain via theBBB depends on the overall difference between the uptakeand efflux processes (Table 1) Brain uptake of drugmoleculesis controlled by various factors including the systemic dispo-sition of the drug as well as the properties of the endothelialcells Thus permeability of endothelial cells and their abilityto metabolize drugs actively regulate the amount of drugcrossing the BBB in both directions [38]

In recent years it has becomewell perceived that the activ-ity of the P-gp in the BBB plays a restrictive role with regard tothe net cerebral uptake of many therapeutic drugs Owing toits unspecific substrate affinities P-gp restricts the achievablecerebral concentration of various medications and may bea crucial factor in the phenomenon of pharmacoresistance[39ndash41] P-gp is a prototypical multidrug resistance (MDR)transporter its discovery was based on its ability to conferdrug resistance to cancer cells P-gp a phosphoglycoproteinacts as an unrestrained energy-dependent efflux pump [5]Given that P-gp efflux accountability can be a key obstacle

for CNS therapeutic drugs to cross the BBB and reach thetarget the interactions of the CNS targeted drugs with theP-gp transporter may lead to the lack of CNS activity asa result of the minimized brain penetration Therefore theestimation and understanding of the significance of P-gp-mediated efflux transporter have become an important stagein the discovery and development of CNS delivery strategies[42]

4 P-gp Efflux Transporter Structure andMechanism of Action

In response to the inefficiency in conventional deliverymechanisms a great amount of research efforts have latelyfocused primarily on the development of new strategies toallow for a greater efficacy in the delivery of drug moleculesto the CNS In particular these research efforts have focusedon the modulation of P-gp efflux transporters within the BBB[43] P-gp is presently themost widely studiedmember of theABC transporter family and has been shown to transport anextensive list of substrates with a great degree of structuraldiversity [44] P-gp is a type of energy-dependent ATPasetransmembrane drug efflux transporter It is a 1280-longamino acid glycoprotein expressed as a single chain structurecontaining two homologous portions of equal length eachportion consisting of 6 transmembrane domains and twoATP binding regions separated by a flexible polypeptidelinker portion [45 46] (Figure 5(a)) [47 48]


CytosolP-gp

COOH

COOH

COOH

MRP1

TM TM

TM

NBD NBD

NBD

TMD0

L0

NH2

NH2

NH2

BCRP

(a)

Outer surface

Inner surface Vacuum cleanermodel

Flippase model

(b)

Figure 5 (a) Structural configuration of P-gp MRP and BCRP[47] (reproduced with permission from Elsevier BV Ltd copy 2005)(b) Diagrammatic representations of the ldquoVacuum Cleanerrdquo andFlippase model of P-gp function [48] (reproduced with permissionfrom Frontiers in Oncology Ltd 2014)

There are numerous models to explain the mechanism ofefflux by the P-gp transporter The three most predominantmodels pore flippase l and the hydrophobic vacuum cleanermodel are commonly used to explain the mechanism ofefflux (Figure 5(b)) The vacuum cleaner model hypothesizesthat P-gp recognizes substrates embedded in the inner leafletof the plasma membrane the substrate is then transportedthrough the protein channel out of the cell [48] Within theperspective of this model P-gp binds directly to the substratemolecules that are located on the plasma membrane andpumps them out of the cell by recognizing the substratesas foreign bodies [49] The pore model is described as aninteraction of P-gp with drugs within the boundaries of thecytosol followed by efflux out of the cell via protein channelsThe hypothesized flippase model explains drug efflux as aldquoflippingrdquo of drugmolecules from the inner leaflet to the outerleaflet of the cell against a concentration gradientThese drugmolecules then undergo diffusion to reach the extracellularspace [49] However the flippase model is the most generallyreceived model and increasing amounts of evidence havemade it the most favored amongst all [50ndash52]

5 P-gp in Schizophrenia Therapy

Antipsychotic drugs and other pharmacological agents usedto treat psychiatric illness must cross the BBB to reachthe target sites within the CNS to be able to exert theirtherapeutic effects Antipsychotic drugs are crucial treatmentoptions for symptoms of schizophrenia The first generationor conventional antipsychotics include drugs that have highaffinity antagonism of dopamine D

2receptors The second

generation antipsychotics or atypical agents include drugswith a lower D

2receptor affinity and a far greater affinity for

other neuroreceptors [53] Recently it has become progres-sively evident that drug transporters situated within the BBBplay a fundamental role in the pharmacokinetics of severaldrugs with therapeutic implications

There are strong indications for an impaired integrityof the BBB in schizophrenia such as increased intracere-bral concentrations of the soluble intercellular adhesionmolecule-1 (sICAM) Furthermore the concentration ofimmunoglobulin and albumin is raised in cerebrospinal fluidin 30 of schizophrenic patients P-gp function has beenreported to be reduced in the progression of neurodegenera-tive diseases [54]

Wang and coworkers [55] conducted a study employingthe abcb1ab knockout mouse model with a functionaldeficiency in P-gp By utilizingATPase activity as amarker forP-gp activity an in vitro study provided evidence that variousatypical antipsychotic drugs such as risperidone and olanza-pine may be effectively effluxed by P-gp In a subsequent invivo study utilizing the abcb1a gene knockout mouse modelresults depicted that P-gp restricted the brain penetration ofolanzapine as the resulting brain concentration was 3-foldhigher in the abcb1a knockout mice than as the comparativecontrol mice [55]

Risperidone is an atypical antipsychotic drug that haspotent antagonistic affinities toward serotonin 5-HT

2and

dopamine D2receptors Risperidone is recognized for its

effectiveness against both positive and negative symptoms ofschizophrenia An in vitro study by Nakagami and coworkers[56] of the activity of P-gp against a range of antipsychoticagents showed that P-gp is likely to influence the absorptionof all atypical antipsychotics to various degrees [56]

In addition to other studies relating to P-gp functionthe activity of the P-gp transporter at the level of the BBBcan be studied in vivo via Positron emission tomography(PET) with [11C] verapamil as a PET tracer PET seems tobe a suitable means of in vivo valuation of P-gp functionalityin humans and allows for the quantification of BBBP-gpfunction in neurodegenerative disorders The PET brainimaging study with the use of [11C] verapamil as a radiotracerwas conducted on schizophrenic patients and a comparativehealthy control group Data obtained from the study showeda regionally reduced [11C] verapamil uptake within thetemporal cortex and basal ganglia of schizophrenic patientsversus healthy controls These results have been interpretedas an increase in P-gp function in the brain of schizophrenicpatients These findings are of immense worth since anincrease in P-gp function may be pertinent for the clinicalprogression of schizophrenia An increase in P-gp function


leads to reduced uptake of antipsychotic agents and may thusbe associated with poor clinical outcomes [54]

A further study by Kirschbaum and coworkers [57] foundthat the ATPase activity assay displayed high affinity of theantipsychotic risperidone for P-gp In vivo studies conductedin mice and humans revealed variations in brain and serumconcentrations for both risperidone and its active metabolite9-hydroxyrisperidone which was recently approved as a newantipsychotic paliperidone In comparison the conventionalantipsychotic haloperidol which displays a high antagonisticactivity at dopamine D

2receptors is poor substrate of P-

gp Behavioral changes in the mdr 1a1b knockout mice incomparison to the wild-type mice allow for the investigationof P-gp-dependent variations in the expression degrees ofthe CNS which leads to functional dispositions Motorimpairment on a rotarod physical task is characteristic ofantipsychotic related D

2receptor antagonism [54 57]

This very hypothesis was applied to mdr 1a1b andwild-type mice after administration of either the knownsubstrate risperidone or a poor substrate haloperidol Resultsrevealed distinctively different profiles in motor effects bythe antipsychotic drug risperidone which was dependent onP-gp expression Brain concentrations of risperidone andits 9-hydroxyrisperidone metabolite were 10-fold higher forthe first three hours in knockout mice versus wild-typemiceThe increased concentration reflects the change in doseresponse seen in the behavioral task The results establishfor the first time the strong association between physi-cal functionality and P-gp-dependent brain concentrationsPharmacokinetic data of this study displayed a 10-fold higherbrain level of risperidone and a 20-fold higher brain level of9-hydroxyrisperidone inmdr1a1bmice as compared to wild-type mice Conclusively antipsychotic drugs are effectivelytransported by the P-gp efflux transporter [57]

In conclusion an additional study was conducted on theatypical antipsychotic aripiprazole To assess the role of P-gp in the distribution and penetration of aripiprazole withinthe BBB mice deficient in the P-gp gene were dosed intra-peritoneally with 2120583gg of aripiprazole Wild type mice wereadministered the same dose as the gene deficient mice Theresults showed that deficiency of P-gp had a drastic effect ondrug concentrations within the brain Thus aripiprazole hasbeen characterized as a transportable substrate of P-gp [53]

6 P-gp Substrates and Inhibitors

In an attempt to estimate the effects of P-gp in vivo a range ofin vitro P-gp assays have been developed so as to categorizecompounds as P-gp substrates or inhibitors (Table 2) Onesuch assay is the Transwell-based assays using polarized celllines such as Madin-Darby Canine kidney (MDCK) cell lineThe MDCK cell line may be stably transfected with humanMDR1 orMdr1a Comparing the efflux ratios betweenMDR1-MDCK and MDCK Transwell assays are able to provide ameasure of the specific human P-gp-mediated efflux activity[57]

Another generally used P-gp in vitro assay is the P-gpATPase assay for assessing drugs that demonstrate P-gp inter-actions as substrates The standard reagent of the ATPase

Table 2 Brief overview of P-gp inhibitorssubstrates and thecorresponding IC50 values of inhibitors

Inhibitor IC50 ReferencesHaloperidol Potent [105]FluoxetineChlorpromazineParoxetineSertraline

Moderate [59 105]

Risperidone9-hydroxyrisperidoneSulpirideZolpidem

Low [59 105]

Loperamidelowast [59]VerapamillowastQuinidinelowast Moderate [58 59]

Prednisonelowast Low [59]Potent (P) inhibition (IC50 lt 10120583M) moderate (M) inhibition (10 120583Mle IC50 lt 50120583M) and low (L) inhibition (IC50 ge 50120583M) lowastNon-CNSInhibitors

assay is a membrane preparation from insect cells that arevastly expressive of human P-gp Functional human P-gpwill transport P-gp substrates across the membrane thusresulting in the release of inorganic phosphates [58] Inaddition the in vitro calcein AM P-gp inhibition assay can beutilized to detect compounds that inhibit the P-gp-mediatedefflux via employing a fluorescent P-gp substrate calceinThecalcein assay is capable of differentiating between various P-gp inhibitors from noninhibitors by measuring the resultantfluorescence of calcein [58]

A further in vitro approach in studying the P-gp activityis the use of P-gp knockout mice in comparison to wild-typemice P-gp knockoutmice are geneticallymodified animals inwhich both genes that are homologous to the human MDR1gene have been disrupted resulting in a viable line of animalmodels An assessment of the brain plasma area under thecurve (AUC) ratio in knockout mice as compared to wild-type mice has become a standard experimental methodologyto determine whether P-gp-mediated efflux poses a possibleobstacle to the activity of CNS targeted drugs in vivo [1 5960]

P-gp exhibits significant capability to bind and transporta wide range of structurally and functionally dissimilar com-pounds Typical drug substrates include typical and atypicalantipsychotics as well as anticancer agents P-gp also interactswith yet another group of hydrophobic agents known aschemomodulators that is calcium channel blockers andphenothiazinersquos Chemomodulators belong to two categoriesthose that are transport substrates themselves and therebycompete for efflux and those that exert their effects bybinding to and blocking drug effluxwithout themselves beingtransported out of the cell [24]

In general P-gp can be inhibited via (i) blocking the drugbinding site competitivelynoncompetitivelyallosterically(ii) by interfering with ATP hydrolysis and (iii) by alteringthe integrity of the cell membrane lipids [45] Based ontheir specificity and affinity P-gp inhibitors are catego-rized into three generations First generation inhibitors are


pharmacological actives which are in clinical use for otherindications but have been shown to inhibit P-gp Second andthird generation inhibitors specifically modulate P-gp withthe second generation inhibitors lacking the pharmacologicalactivity of its first generation counterparts and with a higheraffinity for P-gpThe third generation inhibitors have a 10-foldhigher affinity and potency to inhibit P-gp [24]

7 Novel Drug Delivery Systems andPharmaceutical Excipients Capable of CNSand Intestinal Delivery via P-gp Bypass orInhibition with a Potential Applicability inSchizophrenia Therapy

71 Formulation Excipients Utilized as P-gp InhibitorsApproaches to bypass the P-gp efflux pump may be to com-bine the target drug with either another P-gp pump substrateor an inhibitor on the other hand there is the novel approachof combining the active drugmoleculewith a lipid or polymerexcipient which is capable of P-gp inhibition The initialapproach is effective in its inhibitory potential however itinvolves the use of a second pharmaceutically active agentthat increases the risk of drug-drug interactions thus inretrospect the use of inhibitory excipients has nonspecificpharmacological action and therefore the possibility of sys-temic effects and drug interactions is eliminated [50]

72 Chemosensitizers Chemosensitizers also termed rever-sal agents are one such approach they inhibit the effluxpumpand increase the absorption of drugs intracellularly and thusthe coadministration with clinically relevant compounds hasbecome a common practice [61] Chemosensitizers functionby acting as competition at the P-gp substrate binding siteor by blockade of ATP hydrolysis drugs such as verapamilcyclosporine A and antisteroidal agents such as tamoxifenare classified as 1st generation P-gp modulators Howeverhigh concentrations of these agents are required for this pur-pose and thus lead to pronounced side effects thus the devel-opment of 2nd generation chemosensitizers was promptedThis nevertheless proved to exhibit the same limitations

To circumvent limitations observed with the 1st and 2ndgeneration P-gp chemosensitizers 3rd generation chemosen-sitizers have been developed utilizing the supremacy ofcombinational chemistry and Structure Activity Relation-ships (SARs)These agents are noncompetitive inhibitors thatresult in alterations in protein conformation thus modu-lating P-gp substrates they include elacridar and tariquidaramongst others [62] Further research conducted depictedevidence that drug delivery systems in combinationwith P-gpmodulators could considerably enhance pharmacokinetics ofthe P-gp modulator and in addition reduce the pharmacoki-netic interactions with P-gp substrates Cremophor EL wasone of the excipients employed in the above mentioned studywhich showed promising activity as a P-gp modulator [62]Furthermore in an experimental study conducted by Chooand coworkers tariquidar a P-gp modulator in combinationwith propylene glycol 5 dextrose and ethanol was ableto inhibit P-gp function at the BBB in high doses [63] thus

displaying a possible application in improving CNS perme-ability of drugs employed in neurodegenerative diseases Inanother research study it has been shown that GF120918(elacridar) a known 3rd generation P-gpmodulator is capableof increasing the brain uptake of paclitaxel (P-gp substrate) 5-fold [32]

73 Natural Polymers The natural gums are classified aspolysaccharides that consist of multiple sugar groups thatbonded together to create much larger molecules they offerthe advantages of being sustainable biodegradable andbiologically safe these natural gums are known to form gelsthat depict a high degree of network formation Gums arecapable of undergoing grafting and crosslinking reactionsand through such reactions they may form hydrogels xero-gels and nanoparticles which have a very important functionin the inhibition of the P-gp efflux transporter [63]

Chitosan a cationic polysaccharide in combination withnucleotides to form nanosystems may enhance the perme-ability of drug molecules into the CNS via opening of tightjunctions and the formulation of nanosystems incorporatingchitosan and nucleotides will enable this purpose [64]

Natural polymers such anionic gums for example xan-than and gellan gum as well as alginates have been shown toinhibit the action of the P-gp efflux pump at concentrationsof 005 and 05mgmL respectively [65] In the presenceof xanthan gum studies have shown increased concentrationof P-gp substrates such as vinblastine and doxorubicin Algi-nate flavicam demonstrated an increase in the intracellularconcentration of doxorubicin in everted gut sac cells [66]

74 Synthetic Polymers Synthetic polymers are synthesizedvia polymerization reactions and the modification of naturalpolymers or via the complexation of natural polymers withnaturally occurring agents such as fatty acids [66] Syntheticpolymers such as PEG 400 at concentrations between 1and 20 increased accumulation of digoxin due to theinhibition of the P-gp drug efflux pump [67 68] Similarstudies conducted employing Pluronic P85 and Vitamin ED-120572-Tocopheryl polyethylene glycol 1000 succinate on thedigoxin uptake in rats have further proven that pluronicblocked copolymers are capable of inhibiting the P-gp effluxpump and enhancing substrate uptake [69] Furthermorestudies have shown that pluronic P85 has an inhibitory actionon the ATPase enzyme that is involved in the functioning ofthe P-gp efflux pump proteins thus resulting in inhibitoryreactions between these proteins and the P-gp substrates [70]In a study conducted by Batrakova and coworkers who haveshown the increased brain concentration of digoxin in mdr1knockout mice and wild type mice treated with Pluronic P85it was clearly demonstrated that Pluronic P85 delayed theresidence time and concentration of digoxin in the brain [71]Commonly occurring polymers that act as P-gp inhibitors arelisted in Table 3

Research studies have been conducted to evaluate theinhibitory properties of PEG on the P-gp efflux pump Thestudy involved the grafting PEG to polyethyleneimine (PEI)and then undergoing a thiolation reaction employing 120574-thiobutyrolatone to formulate a novel grafted thiomer The


Table 3 Summarized list of polymer amp surfactant P-gp inhibitorsand their mechanism of actionPolymer andsurfactant based P-gpefflux inhibitors

Applications References

Natural polymers

Xanthan gumGellan gumAlginates

Inhibition of the P-gp effluxtransporter by the presenceof polysaccharided-mannose monomersincreasing concentration ofsubstrates for examplevinblastine anddoxorubicin

[65]

Synthetic polymers

PEG 400PEG-PEIPEG 300

Changes themicroenvironment ofCaco-2 cell membranesleading to modifications inmembrane fluidity

[65 66]

Pluronic P85

Results in ATPaseinhibition and ATPasereduction as well asmembrane fluidization

[66 68 69]

Thiomers

Thiol groups interact withcysteine in the P-gptransmembrane channelforming disulfide bondsThus the allosteric changeblocks efflux

[71]

grafted PEG was then evaluated based on its effect on thetransport of Rhodaminendash123 a well-known P-gp substrateResults depicted that the cellular uptake of Rhodamine-123was improved with the grafted-thiolated PEG as compared tofree drug solutions

Oral administration of many drug substances is limiteddue to the poor bioavailability and systemic uptake whichis directly linked to the presence and action of the P-gpefflux pump In an attempt to overcome this limitation therehas been the development of P-gp pump inhibitors howeverdue to the abovementioned set back of requiring high dosesnone of them have been approved for oral administrationdue to the risk of systemic side effects Thus polymeric P-gp inhibitor incorporation into drug delivery systems asexcipients provides a valuable approach they show a highinhibitory potential and due to their great molecular weightsthey are not absorbed from the gastrointestinal system andthus eliminate any possible systemic effects Previous studiesdetermined the inhibition of P-gp by PEGrsquos by their effecton the elevated permeability of substrate drug moleculessuch as taxol and doxorubicin within caco-2 monolayers[72] PEGylated sorbitans that are esterified with fatty acidsare commonly known as polysorbates The most extensivelystudied group of the Polysorbates is polyoxyethylene sorbi-tans monolaurates known by the trade name Tween theseagents have been found to enhance the accumulation ofdaunorubicin within tumor cells [66]

Poloxamers also fall within the category of syntheticpolymers and are also known as Pluronics Specifically

Pluronic P85 has been studied for its inhibitory effect onthe function of the P-gp efflux pump Two main areas thatP85 is used for its inhibitory properties are in the BBB andcancer chemotherapy [66] The mechanism of inhibition hasbeen dedicated to a reduction in ATP and inhibition ofATPase enzymes as well as lipid membrane fluidization [7071] Pluronic brings about a reduction in ATP levels withinbovine endothelial cells the ATP depletion was reasoned tobe as the result of the inhibition of cellular metabolism [73]Additionally mixedmicelles synthesized from a combinationof poloxamer 407 and D-120572-Tocopheryl polyethylene glycol1000 succinate (TPGS 1000) have the potential of elevating theclinical efficiency of drugs by increasing the amount of drugin the interior of the cell by inhibiting P-gp efflux transporters[74] TPGS 1000 is classified as a water soluble vitamin thatconsists of a lipophilic head and hydrophilic PEG tail Themechanism by which TPGS 1000 inhibits the P-gp pump hasbeen proposed as a combination of membrane fluidizationATPdepletion and prevention of substrate binding Researchon the effect of pluronic block polymers on the accumulationof digoxin has proven the hypothesized inhibition of P-gp efflux transporters by Pluronic polymers The treatmentof various substrates with Pluronic polymers displayed anincrease in apical to basolateral transport thus displaying P-gp inhibition [66 70 71]

Thiomers yet another group of synthetic polymers arecharacterized as polymers containing a thiol moiety withintheir chemical structure the presence of the thiol moietyallows for the formation of disulfide bonds between thecysteine groups of the P-gp pump for example 120572-chitosan-thiobutylamidine [75] The mechanism of thiomer mediatedinhibition of the P-gp efflux pump is depicted in Figure 6Improved transmucosal transport of Rhodamine-123 a P-gpsubstrate in the company of thiolated chitosan produced bylinking of amino groups of chitosan and thiol groups [76] wasdisplayed by Bernkop-Schnurch et al due to P-gp transporterinhibition Thiomers are not absorbed from the GIT due totheir high molecular weight therefore systemic side effectsare eliminated and their use as pharmaceutical excipientsfor their P-gp inhibitory properties is greatly beneficial [72]As described above the P-gp efflux pump is made up of12 transmembrane units these units in turn form channelsthrough which P-gp substrates pass through to exit thecell two of the 12 units display cysteine subunits Thiomersare theorized to enter the channels of the P-gp pump andthereafter form disulfide bonds with the cysteine subunits inthis manner the transport of drug molecules out of the cell ishindered and thus there is an inhibition of P-gp efflux pumpaction [64] Thiolated chitosan is a directly compressibleexcipient which may therefore be formulated into matrixtablets [76]

75 Solvents and Surfactants Both surfactants and solventsact by interaction with the polar heads of the lipid bilayersthereby adjusting hydrogen bonding and ionic forces andhave the potential to insert themselves between the non-polar tails of the lipid bilayer These interactions cause thefluidization of the lipid membrane and thus P-gp inhibitionNonionic surfactants such as Tween and Span possess P-gp transporter inhibitory potential these agents are also


Nonthiolatedpolymer

Thiolatedpolymer

Weak noncovalentbond

Strongdisulfide bond

Mucousmembrane

Figure 6 Mechanism of inhibition of the P-gp efflux pump [117](reproduced with permission from Elsevier BV Ltd copy 2013)

hydrophobic and thus rendered less toxic [77] Surfactantsare furthermore important in the formulation process ofnanoparticles Various research outputs have shown that theefficiency of surfactants as P-gp inhibitors is based on theirrespective chemical structures Surfactants such as SolutolHS15 Tween 80 and Cremaphore EL contain Polyethyleneglycol on the hydrophilic portions of their structures whichhave displayed the ability to increase intracellular concen-trations of epirubicin in human colorectal carcinoma cellsthereby confirming that surfactants act as P-gp modulators[62] In a study conducted by Rege and coworkers [78] theeffect of Tween 80 Cremophor EL and vitamin E TPGSon the P-gp efflux transporter in caco-2 cell monolayerswas investigated Results showed that all three surfactantsinhibited P-gp and Tween 80 and Cremophor EL increasedthe apical to basolateral permeability of Rhodamine 123(P-gp substrate) within a concentration range of 0-1mMWhereas vitamin E TPGS contributed an inhibitory effect ata concentration of 0025mM [78]

8 Drug Delivery Systems with P-gpModulatory and Enhanced IntestinalAbsorption Applications

The following section will focus on the strategic design ofdrug of delivery systems studied for their aptitude to enhancebioactive delivery through the intestinal epithelia by P-gpmodulation andor inhibition with a future applicability inschizophrenia therapy

81 Bestatin-Improved Intestinal Absorption by Coadministra-tion of a P-gp Inhibitor A study by Huo and coworkers [79]

has shown the enhancement effect of P-gp inhibitors on theintestinal absorption of bestatinThe study showed that whenbestatin and cyclosporine A were coadministered orally theresultant plasma concentration of bestatin was considerablyincreased CyclosporineA andVerapamil commonly utilizedP-gp inhibitors can eliminate the efflux pump mediated byP-gp resulting in improved intestinal absorption of the coad-ministered P-gp substrate The study by Huo and coworkers[79] displayed a 90 increase in bestatin intestinal absorptionseen in the Cmax and AUCwith the addition of cyclosporineA [79]

82 Enhanced Intestinal Absorption of Ganciclovir by P-gpInhibition Using Pharmaceutical Excipients Several studieshave shown that P-gp inhibitors such as verapamil andcyclosporine A are capable of enhancing the bioavailabilityof a variety of drugs However such inhibitors are pharma-cologically active agents and thus may cause toxic effects Inaddition these agents are absorbed into the bloodstream andcan interact with P-gp in other organs that it is expressed in

On the other hand pharmaceutical excipients which areutilized as inert excipients in drug delivery formulations arebeing investigated as superior class of P-gp inhibitors Severalstudies have shown that these excipients can greatly improvethe intestinal absorption of a wide range of drugs by P-gpinhibition

These excipients are nonabsorbable thus there will be nounnecessary P-gp inhibition in other organs A study con-ducted by Li and coworkers [80] studied the effects of com-mon excipients on the intestinal absorption of ganciclovir asubstrate of P-gp in rats The in vitro transferal from mucosato serosa as well as the in situ transepithelial permeation wasevaluated Selected excipients within a concentration rangeof 01ndash1 wv were shown to increase the concentration ofganciclovir transported in an everted gut sac model

Results depicted a significant increase in permeability ofganciclovir by all excipients employed in the studyThe effectsof EL-35 and F-68 were dose-dependent but that of PEG 400and Tween 80 were not The results observed confirm thatthe improvement of intestinal absorption of ganciclovir viathe use of excipients is due to inhibition of P-gp inhibitionmediated drug efflux The mechanism of F-68 inhibition ofP-gp is due to its blocking effect on the binding site of the P-gp efflux transporter whereas PEG 400 tween-80 and EL-35are due to alteration in the membrane fluidity of P-gp [80]

83 Self-Emulsifying Drug Delivery Systems This is anotherdrug delivery approach that may prove useful in bypassingthe P-gp pump duemainly to the presence of surfactants suchas Tween 80 that have been identified as P-gp inhibitors [78]SMEDDrsquos consisting of vitamin E (oil phase) and surfactantshave been shown to enhance the solubility and bioavailabilityof paclitaxel (a P-gp substrate) owing to their P-gp inhibitorsactivity

An advantage of using SMEDDrsquos is their capability toincorporate and solubilize high concentrations of P-gp inhib-itors Many studies have been conducted to improve theoral bioavailability of this chemotherapeutic agent so as toincrease clinical outcomes it has been proven that P-gp


plays a vital role in the bioavailability of paclitaxel the studyconducted by Woo and coworkers shows that the use ofKR-30031 a verapamil analog with P-gp inhibitory effectsin combination with paclitaxel improved the bioavailabilityof the later [81] Nanocapsules have been used as a drugdelivery system to improve the oral bioavailability of theP-gp substrate Tacrolimus which was incorporated intonanocapsules with the use of polymethacrylate polymersResults depicted that the bioavailability was between a rangeof 245- and 49-fold compared to the commercially availableformulation [2]

84 Double Coated Nanocapsules for Enhanced IntestinalAbsorption and Bioavailability of a P-gp Substrate An exper-imental study performed by Nassar and coworkers [2] pro-poses the use of double coated nanocapsules to improve thebioavailability of a P-gp substrate Tacrolimus Using caco-2 cells and intestinal rat segment the effect of encapsulationof Tacrolimus on P-gp was evaluated The double coatednanocapsules prevented its molecular recognition by the P-gp efflux transporter in caco-2 cells The conclusive resultsshow that the nanocapsule delivery system is a great platformfor intestinal absorption of lipophilic drugs which are P-gpsubstratesThe oral bioavailability of Tacrolimus was 49- and245-fold greater when compared to a marketed product [2]

85 Novel Polymeric P-gp Inhibitor for Enhanced IntestinalDrug Delivery Many drugs are unable to be administered viathe oral route owing to poor absorption into the systemiccirculation due to intestinal P-gp efflux pumps In order tocircumvent this obstaclemany types of efflux pump inhibitorshave been developed Yet many of these inhibitors have notbeen approved for oral use due to their systemic side effectsA noteworthy alternative would be polymeric based effluxpump inhibitors displaying greatly efficient inhibitory actionand no systemic side effects because it is unabsorbed into theintestine due to its high molecular mass

In a study conducted by Iqbal and coworkers [72] a novelthiolated copolymer thiolated PEG-g-PEI copolymer wassynthesized The novel thiolated copolymer showed a sig-nificantly greater effect on the intestinal absorption of Rho-123 a P-gp substrate as compared to other P-gp inhibitorsIn addition the thiolated copolymer was able to increase theintestinal uptake of Rho-123 up to 326-fold in comparison toa system lacking a P-gp inhibitor In addition to enhancingthe absorption of Rho-123 the novel thiomer was also capableof decreasing the basolateral to apical transport across therat intestinal mucosa segment The study has thus providedevidence that the novel thiomer has a great applicability inimproving bioavailability of P-gp substrate drugs [72]

86 Influence of Intestinal P-gp on Absorption of Furosemidea P-gp Substrate Furosemide is a loop diuretic employedin the clinical treatment of congestive heart failure andhypertension Pharmacokinetics of furosemide show that ithas incomplete absorption from the gastrointestinal tractafter oral dosing P-gp efflux pumps have been implicated asthe possible cause for reduced absorption however no com-plete evidence existsThe intestinal absorption of furosemide

was evaluated in the presence and absence of verapamilutilizing the rat intestinal sac model in an experimental studyconducted by Al-Mohizea [82]

Results obtained from the study depict low drug perme-ability in the noneverted rat intestinal sac This replicatesthe drug transference from the mucosal to serosal regionwhich imitates the in vivo environment In contrast whenobserved in the everted rat intestinal sac drug displayed anoticeably greater transport as compared to transport acrossthe noneverted intestinal sac These results clearly indicatethe involvement of the P-gp pump and because the definedfunction of the P-gp efflux transporter is to pump drug backinto the intestine subsequent to absorption the observedoutcomes indicate a greater transintestinal permeation fromthe serosal to mucosal regionThe ratio of serosal to mucosaland mucosal to serosal permeability was discovered to be 56and this was advocated for the possible role of P-gp effluxtransporter in the intestinal uptake of furosemide The effectof verapamil hydrochloride a P-gp efflux pump inhibitor onfurosemide absorption was employed to confirm the resultsobtained from the intestinal sac model experiment

It was shown that the presence of verapamil increasedthe mucosal to serosal transport of furosemide noticeablycompared to the control lacking verapamil This observationis due to the inhibitory effect of verapamil on the P-gpefflux pump which prevents transport of drug back intothe mucosal region The ratio of serosal to mucosal andmucosal to serosal permeability was reduced from 56 in theabsence of verapamil to 128 in its presence These resultsconfirm the mechanistic effect of the P-gp efflux pumpon intestinal absorption Furthermore the current studyevaluated the effect of Tween 80 and HP120573CD two com-monly employed pharmaceutical excipients on the intestinaluptake of furosemide The results displayed a permeationimprovement effect for Tween 80 but not for HP120573CD Thisin turn inferred a substantial increase in the mucosal toserosal permeability of furosemide Tween 80 was shown todecrease the ratio of serosal mucosal to mucosal serosalpermeability (56 to 108) This provides evidence that Tween80 is a noteworthy P-gp efflux pump inhibitor [82]

9 Drug Delivery Systems with P-gpModulation and Enhanced BBB Absorption

The following sectionwill focus on drug delivery systems thathave been studied for their unique ability to enhance BBBpermeability of drug agents via P-gp inhibition andor bypasswith a prospective application in schizophrenia therapy Theeffective noninvasive treatment of neurological diseases isfrequently restricted by poor access of bioactives into thecentral nervous system (CNS) Many therapeutic agents donot freely permeate into brain tissue due to the presenceof the BBB and its associated P-gp efflux pump transporterRecent advances in drug delivery technology have providedpromising solutions to overcome these challenges

The use of drug delivery systems with the ability to bypassor inhibit the P-gp efflux transporter has shown a greatimprovement in CNS bioavailability and hence enhancedtherapeutic outcomes Furthermore nanocarriers ranging


from polymeric nanoparticles solid lipid nanoparticles lipo-somes dendrimers and micelles have been studied for theirability to deliver CNS therapeutics and have displayed successin the treatment of CNS diseases such as brain tumors andalzheimerrsquos [83] Hence we propose the use of these deliverysystems in the treatment of schizophrenia so as to bypass theBBB and its efflux transporters

91 Nanocarriers Nanoparticles can gain access to the brainvia numerous mechanisms These mechanisms acting eitheralone or in combination can explain the transport of ther-apeutically bioactive agents across the BBB (i) adsorptionand pooling of nanoparticles in the capillaries of the brainfollowed by adsorption to the capillary wall which providesa concentration gradient across the blood capillaries locatedin the brain cells therefore this may enhance the transportof bioactives across the endothelial cell monolayer andthus increase the uptake of the bioactive into the brain(ii) receptor-mediated endocytosis of nanoparticles acrossthe BBB followed by internalization of the complex andrelease of the bioactives within brain cells (iii) transcytosisnanoparticles with bound bioactives which can undergotranscytosis through the endothelial cell monolayer and gainaccess to the brain capillaries (iv) inhibition of the P-gpefflux transporter and coating nanoparticles with specific P-gp inhibitory substances such as polysorbate 80 that maypossibly inhibit the P-gp (v) membrane permeabilizationeffect that involves solubilization of the endothelial celllipids via the use of surfactants which leads to membranefluidization and enhanced permeability of the BBB and (vi)disruption of the BBB thus opening tight junctions locatedbetween endothelial cells of the BBB nanoparticlesmay assistin permeation of bioactives through tight junctions [84]Nanocarriers are colloidal systems that include polymericmicelles nanoparticles lipid nanocapsules and liposomesamong others Many of these systems have been designedand developed for indications in various CNS disorders toenhance brain uptake of the CNS targeted bioactives via P-gp transporter activity modulation

92 Surfactant-Polymer Nanoparticles Overcome P-gp-Medi-ated Drug Efflux Nanoparticles improve the therapeuticefficacy of an encapsulated drug by increasing and prolongingthe delivery of the drug within the cell Aerosol OT-alginatenanoparticles were employed in evaluating their deliverycapabilities in brain tumor cells overexpressing P-gp Rho-damine 123 and doxorubicin were employed as model P-gpsubstrates Uptake studies using Rhodamine loaded nanopar-ticles showed a substantial increase in drug accumulationin resistant cells The energy-dependent nanoparticle accu-mulation within cells proposes the contribution endocytosisin nanoparticle uptake Nanoparticle doses of greater than200120583gmL were shown to be the minimum concentration toimprove drug accumulation [85 86]

93 Lipid-Based Nanoparticles Paclitaxel loaded lipid nano-particles (Figure 7) utilizing Brij 78 displayed IC

50values

9-fold greater than when formulated with taxol The studyestablished that lipid nanoparticles were able to inhibit

100nm

5nm

Figure 7 TEM images of lipid based nanoparticles arrows showthe lipid bilayer thickness [87] (reproduced with permission fromElsevier BV Ltd copy 2013)

P-gp due to the presence of Brig 78 which was utilized inthe synthesis of the microemulsion precursor Temporaryand reversible reductions in ATP were observed with blanknanoparticles and free Brig 78 Therefore the greater degreeof P-gp substrate accumulation was elucidated by a synergis-tic combination of nanoparticle with Brig 78 where nanopar-ticles improve the brain uptake of the bioactive by partiallybypassing the P-gp transporter and drug efflux is restrictedvia the release of Brig 78 from the nanoparticles [50 62 87]

In other studies lipid nanocapsules loaded etoposidewere synthesized due to their hypothesized reversal of mul-tidrug resistance by the use of P-gp inhibitory surfactantsduring formulation P-gp inhibitory activity of the etoposideloaded lipid nanocapsules was independent of size The pro-posed mechanism was cell uptake followed by intracellularP-gp inhibition thus allowing for a higher intracellular drugconcentration [88] In a further research study the formu-lation of lipid nanocapsules was achieved by the use of tri-caprylic acid polyethylene glycol 660 and soybean lecithinfor the delivery of the therapeutic agent paclitaxel to caco-2 cells results showed that the oral bioavailability of pacli-taxel was greatly improved possibly due to the ability oflipid nanocapsules to inhibit the P-gp efflux activity thismechanism is primarily due to the fact that the surface layerof nanocapsules being phospholipids thus resulting in P-gpinhibition via P-gp substrate site competition [89]

94 Transferrin-Conjugated Nanoparticles for Delivery acrossthe BBB Transferrin-conjugated nanoparticles of poly(lac-tide)-D-120572-Tocopheryl polyethylene glycol succinate diblockcopolymer were formulated via the nanoprecipitationmethod with encapsulated docotaxel Results from the studyshowed via IC

50data that transferrin-conjugated nanopar-

ticles were 234ndash229 more efficient than the control PLGAnanoparticles Thus based on results obtained transferrin-conjugated nanoparticles showed to be effective in deliveryof drugs across the BBB [90]

95 Paclitaxel-Polymer Micelles to Overcome Multidrug Resis-tance (MDR) Micelles form from the spontaneous asso-ciation of amphiphilic copolymers in aqueous phase and


Figure 8 TEM micrographs showing the surface morphology ofdrug loaded micelles [91] (reproduced with permission from Else-vier BV Ltd copy 2011)

are characterized by a diameter no greater than 100 nm(Figure 8) The attractive force that leads to micellization isbased on the interaction between the electrostatically neutraland hydrophobic portions of the copolymer Self-assembly ofthe micelle only begins when the copolymer concentrationreaches a threshold value generally referred to as the criticalmicelle concentration (CMC) [91] Verapamil is a knownP-gp inhibitor as well a reversal agent used in reversal ofresistance associated with P-gp Within the context of thisstudy paclitaxel a P-gp substrate in combination with ver-apamil was encapsulated into micelles utilizing DOMC-FA(deoxycholic acid methylated chitosan-Folic acid) Resultingdata showed that the conjugation of folate on to micellesdisplayed a higher brain tumor cell uptake of the loadedmicelles possibly via folate receptor-mediated endocytosisMicelles consisting of the combination of verapamil andpaclitaxel showed a higher cellular accumulation of paclitaxelas compared to micelles lacking verapamil [92]

In another study mixed micelles of hydrophobic andhydrophilic pluronic L61 and F127 with encapsulated dox-orubicinwere formulated Results observed depicted elevatedcellular concentrations of drug to P-gp inhibition displayedvia modification of intracellular drug transport [86]

96 Polyethylene Glycol-660 Hydroxystearate NanocapsulesNanocapsules encapsulated with etoposide (substrate) incombination with P-gp inhibiting surfactants namely PEG-HS (polyethylene glycol-660 hydroxystearate) were formu-lated with results depicting an increased bioavailability ofetoposide [89 93] Further studies showed that lipid nanocap-sules of paclitaxel formulated by triglycerides of capric andcaprylic acids increased the uptake of drug molecules byMDR1 cells the half-life of paclitaxel was also prolonged from21 minutes initially to 5 hours [83]

97 Immunoliposomes in Bypassing P-gp The overexpres-sion of P-gp has been associated with the development ofmultidrug resistance in cancer cells Methods employed inovercoming the multidrug resistance frequently involve thecoadministration of inhibitors of the P-gp transporter (Fig-ure 9(a)) Within the context of this study the hypothesis

that immunoliposome-based drug delivery systems may beemployed as alternatives to overcome multidrug resistancehas been explored Since immunoliposomes penetrate targetcells via receptor-mediated endocytosis which in turn allowsfor the bypass of membrane related P-gp transporters target-ing of immunoliposomes was accomplished by via the useof an antitransferrin receptor monoclonal antibody (OX26mAb)The incorporation of radiolabelled digoxin andOX26-immunoliposomes improved the cellular uptake of digoxinby a factor of 25 in immortalized rat brain endothelial cellsThe cellular uptake aswell as intracellular accumulation of thedigoxin loaded liposomes was determined by acid washingof the cells and further confirmed via confocal microscopystudies This in vitro study proposes that immunoliposomebased drug delivery systems can be utilized to bypass P-gpand therefore deliver bioactives to the cytosol of target cells[94] Furthermore there is the novel approach of combiningsubstrates and P-gp inhibitors within liposomal deliverysystems clinical trials were performed via the formulationof liposomes encapsulating PSC 8339 a recognized P-gpefflux inhibitor in combination with the drug moleculedoxorubicin results observed depicted an increase in drugdelivery potential with no alteration to the pharmacokineticor pharmacodynamic character of the drugmolecule [95 96]

98 PAMAM-Drug Complex for Delivery across the BBBDendrimers are defined as synthetic macromolecules thathave a well-defined structural configuration It is made up ofa centrally located core and branched units that stem fromthe core (Figure 9(b)) [66 97]Themechanismbywhich den-drimers inhibit P-gp is via endocytosis the dendrimer passesinto the cell interior this inhibition process could be due tocell membrane alterations and ATPase inhibition researchhas shown that P-gp substrates that are encapsulated withindendrimers show an increased intracellular concentration[61] Polyamidoamine (PAMAM) dendrimers belong to anew avenue of P-gp inhibition research these dendrimers areknown to improve the solubility of low solubility drugs In thecurrent study doxorubicin was chosen as the bioactive agentPolyamidoamine (PAMAM) dendrimers were exploited asan effective carrier of doxorubicin Data obtained from thefluorescence intensity assay and fluorescent microscopy dis-played that cellular uptake of the PAMAM-doxorubicin com-plex was 6-fold greater than that of free doxorubicin Theseresults provide evidence that the novel PAMAM-bioactivecomplex is a simple yet highly efficacious system with a greatcapability to cross the BBB and thus delivery CNS targeteddrug successfully [98]

Propanolol a P-gp substrate was encapsulated withinPAMAM dendrimers due to its poor solubility Conjugationof propanolol with PAMAM dendrimers was found to allowfor bypass of the P-gp efflux pump and therefore enhance thedrug concentration within target cells [99 100]

99 Poly(DL-lactide) Nanosuspensions of Risperidone Nano-suspensions are dispersed systems comprising fine particlesof drug molecules in the form of crystals Nanosuspensionsare known commonly to incorporate highly lipophilic com-pounds these therapeutic agents are stabilized in solution via


Endosomalrelease

Free digoxin Liposomaldigoxin

P-gp P-gp

(A) (B)

(a)

(A) (B)

Core

Branchingpoints

Surfacegroups

Molecularcargo

123 z

zz

zzzzzz

zzz

zz z z z z z

zz

zz

z

G3 asymp 50nm

(b)

Figure 9 (a) (A) P-gp interacts with substrates in the plasma membrane and digoxin (substrate) is effluxed from the lipid bi-layer(B) Cellular uptake of digoxin facilitated by Immunoliposomes-targeted to transferrin receptor and taken up via receptor-mediatedendocytosis [94] (reproduced with permission from Drug Targeting Ltd 2002) (b) (A) 2D Schematic representation of a dendrimer (B)3D representation of a dendrimer [100] (reproduced with permission from Elsevier BV Ltd copy 2009)

the use of surfactants The large surface area afforded by thefine particles assists in enhancing bioavailability to the braintissue atovaquone coated by polysorbates in the form of ananosuspension increased activity in mice presenting withencephalitis [83] Employing Pluronic F-68 (P-gp inhibitor)nanosuspensions were formulated containing risperidoneand poly-lactide they have been found to display betterclinical outcomes in psychotic disorders via P-gp inhibition[101]

910 Natural Vesicular Exosomes as Drug Delivery Systems toPossibly Bypass P-gp Efflux Extracellular vesicles are definedas cell derived membrane vesicles with a characteristic(phospho) lipid bilayer that allows for cell to cell commu-nication Microvesicles are sized between 50 and 2000 nmwhereas exosomes are between 40 and 150 nm Exosomesare produced by the formation of intraluminal vesicles in

multivesicular bodies Fusion of multivesicular bodies withthe plasma membrane results in secretion of intraluminalvesicles which are in turn referred to as exosomes oncereleased into the extracellular space Due to their respectivesizes and natural functionality microvesicles and exosomesseem to be model candidates for drug delivery [102] A studyconducted by van Dommelen and coworkers provided theinitial evidence of biotechnological modification of vesicularexosomes immature dendritic cells was derived from mousebonemarrowas a source of exosomesThesewere then loadedwith exogenous siRNA for delivery The BBB was chosen asthe target site due to it being a vital obstacle to the deliveryof drugs to the CNSThe study displayed specified delivery ofsiRNA toneurons in the brainwith no corresponding toxicityIn another study performed exosomes were used to deliveranti-inflammatory drugs to the brain via the intranasal routeIt was proven that exosomes administered in this manner are


Table4

Drugdeliverysyste

mPo

lymer

Drug

Application

References

Nanocarrie

r(nanosph

eres)

Polyethylene

glycol

Polybu

tylcyano

acrylatealginate

polyethylene

glycolpolylactic

ndashco-

glycolicacidand

polylacticacid

Doxorub

icinclozapinem

etho

trexate

saqu

inavir

andzido

vudine

Drugmoleculeisd

elivered

tothec

ell

nucle

usandthus

avoids

recogn

ition

bythe

BBBandintestinalP-gpeffl

uxpu

mp

[83106ndash

108]

Lipo

somes

Phosph

olipidsa

ndcholesterol

Epiru

bicin

cisplatinm

etho

trexate

anddo

xorubicin

ItinhibitsP-gp

efflux

transporterb

yinteractionwith

phosph

olipidsthes

ystem

may

also

incorporateP

-gpinhibitors

[9596]

Polymer

nano

particles

Acrylic

polymerssuchas

poly-butyl-cyano

acrylate(PBC

A)

Loperamidea

nddo

xorubicin

Itbypasses

theP

-gpdu

eititsnano

size

[106]

Dendrim

ers

Manno

sylatedpo

ly(propyleneim

ine)

andpo

lyethylene

glycol-poly(am

idoamine)

Vinb

lastinedo

xorubicin

and

prop

rano

lol(intestinal)

ItinhibitsP-gp

efflux

bybypassingthep

ump

[97ndash99]

Nanogels

Catio

nica

ndno

n-ionicp

olym

ers

NVPNIPAM

Antise

nsep

hospho

rothioate

oligon

ucleotides

(SODN)a

nd5-flu

orou

racil

Itallowsfor

theincorpo

ratio

nof

P-gp

inhibitors

Polysorbatec

oatin

gof

nano

gelincreases

brainaccumulationfro

m018

to052

[83109]

Micelles

Pluron

icsL

61andF127

andP8

5Doxorub

icindigoxinpaclitaxel

riton

avir

andvinb

lastine

(1)Itinh

ibits

P-gp

efflux

andalso

involves

intracellulard

rugtransportm

odificatio

ntherebyavoiding

theP

-gpeffl

uxpu

mp

(2)D

rugperm

eabilityin

mon

olayered

BBB

mod

elby

P-gp

substrates

increasedfro

m16

-to

29-fo

ldN

ochange

indigoxin

concentrationin

mdr1k

nockou

tmice

[83110

111]

Hydrogels

(hydroxyprop

yl)M

ethacrylam

ide

Cyclo

sporineA

anddo

xorubicin

ItinhibitstheP

-gpeffl

uxtransporterb

yincorporationof

drugssuchas

cyclo

sporine

AthatareP

-gpinhibitors

[112]

LipidNanocapsule

PEG-H

S(polyethyleneg

lycol-6

60hydroxystearate)poly-methacrylate

polymersandHPM

CEtop

osidea

ndtacrolim

us(1)Itinh

ibits

P-gp

efflux

byincorporationof

surfa

ctantb

ased

P-gp

inhibitors

[8389]

Triglycerid

esof

capricandcaprylic

acidsSolutol

Paclitaxel

(2)P

aclitaxelup

take

increasedin

MDR1

expressin

gcellsthe

half-lifeinbrain

prolon

gedfro

m21min

togt5h

Self-em

ulsifying

drug

deliverysyste

ms

Poly-m

ethacrylatep

olym

ers

Paclitaxeland

yacrolim

usItinhibitsP-gp

efflux

byincorporationof

surfa

ctantb

ased

P-gp

inhibitorsfor

exam

pleTw

een

[113114]

Medium

chaintriglycerid

ePE

G40

0po

lysorbate8

0andcrem

opho

rEL

Penfl

uridol(schizop

hreniatherapeutic

agent)

Itenhances

solubilizationof

drug

andthus

effectiv

ebrain

concentrations

Capm

ulMCM

-C8crem

opho

rELand

pluron

icL-121

Irinotecan

Itincreasedoralbioavailabilityby

P-gp

mod

ulation

Nanosuspension

Pluron

icF6

8Risperidon

eP-gp

efflux

inhibitio

nby

employing

polymersthatinh

ibittheP

-gptransporter

such

aspluron

ic

[101]


potential delivery vehicles for small molecules by enhancingbiological stability and passage across the BBB these systemsmay be extended to include a wider range of therapeuticagents [103]

Findings from research studies conducted thus far indi-cate that a vesicular exosomal-based formulation could be avaluable implement in future for the treatment of neurode-generative disorders [104] A comprehensive summary of thevarious drug delivery systems polymers and drugs employedin their formulation process and their respective applicationsis provided in Table 4

10 Conclusions

Central nervous system (CNS) disorders such as schizophre-nia are becoming increasingly prevalent with limitations insocial and physical functionality of patients being reducedTreatment outcomes associated with schizophrenia therapyare reduced due to pharmacoresistance which leads to areduction in patient compliance The P-glycoprotein (P-gp)efflux transporter located within the blood-brain barrierrestricts the uptake of drugs and other molecules within theCNS furthermore it has been implicated in the occurrence ofpharmacoresistant schizophreniaTherefore research studiesconducted in regards to the role of the P-gp transporter inCNS drug delivery prove to be a noteworthy avenue so asto improve schizophrenia treatment outcomes The investi-gation of pharmaceuticals and novel drug delivery systemsperformed within the context of other CNS related diseasestates as reviewed has a promising applicability to the futuretherapy of pharmacoresistant schizophrenia due to P-gpefflux activity Although P-gp modulating chemosensitizersshow a noted reduction in P-gp function the use of highdoses to achieve such an effect becomes a limiting factor totheir use due to toxic side effects Conversely the use ofnatural and synthetic polymers demonstrates highly efficientP-gp modulatory activity coupled with a pronounced safetyprofile and low cost thus it is evident that these agents havea vast functionality in P-gp modulating systems In additiona great amount of research has been focused on the useof nanotechnology in the bypassing of P-gp to allow forenhanced brain uptake of bioactive agents with majorityof these systems displaying success However the designand development of nanosystems are both time consumingand costly Therefore foreseen future trends lay in thebenefit of applying the reviewed P-gp modulating agents intoconventional delivery systems such as matrix tablets whichoffer the added advantages of ease of administration costeffectiveness and improved patient compliance to treatmentplans as it is a conventional method of drug delivery witha wide array of applications Moreover the need for P-gp modulating systems in schizophrenia treatment is vitalyet there remains a research gap in the development ofdrug delivery systems to combat P-gp efflux of antipsychoticagents at both the intestinal and BBB levels Thus this reviewpoints to the various methods that may be applied in futureschizophrenia drug delivery strategies

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] W Loscher and H Potschka ldquoDrug resistance in brain diseasesand the role of drug efflux transportersrdquo Nature ReviewsNeuroscience vol 6 no 8 pp 591ndash602 2005

[2] T Nassar A Rom A Nyska and S Benita ldquoNovel doublecoated nanocapsules for intestinal delivery and enhanced oralbioavailability of tacrolimus a P-gp substrate drugrdquo Journal ofControlled Release vol 133 no 1 pp 77ndash84 2009

[3] MTakano R Yumoto andTMurakami ldquoExpression and func-tion of efflux drug transporters in the intestinerdquo PharmacologyandTherapeutics vol 109 no 1-2 pp 137ndash161 2006

[4] P H Elsinga N H Hendrikse J Bart W Vaalburg and A vanWaarde ldquoPET studies on P-glycoprotein function in the blood-brain barrier how it affects uptake and binding of drugs withinthe CNSrdquo Current Pharmaceutical Design vol 10 no 13 pp1493ndash1503 2004

[5] E M Taylor ldquoThe impact of efflux transporters in the brainon the development of drugs for CNS disordersrdquo ClinicalPharmacokinetics vol 41 no 2 pp 81ndash92 2002

[6] K de van Wetering A Burkon W Feddema et al ldquoIntestinalbreast cancer resistance protein (BCRP)Bcrp1 and multidrugresistance protein 3 (MRP3)Mrp3 are involved in the pharma-cokinetics of resveratrolrdquo Molecular Pharmacology vol 75 no4 pp 876ndash885 2009

[7] M Demeule A Regina J Jodoin et al ldquoDrug transport to thebrain key roles for the efflux pumpP-glycoprotein in the blood-brain barrierrdquo Vascular Pharmacology vol 38 no 6 pp 339ndash348 2002

[8] A Lalatsa A G Schatzlein and I F Uchegbu ldquoDrug deliveryacross the blood-brain barrierrdquo Current Drug Delivery vol 5no 50 pp 657ndash666 2011

[9] A L Bartels R Kortekaas J Bart et al ldquoBlood-brain barrierP-glycoprotein function decreases in specific brain regionswith aging a possible role in progressive neurodegenerationrdquoNeurobiology of Aging vol 30 no 11 pp 1818ndash1824 2009

[10] Y-C Lin V L Ellingrod J R Bishop and D D Miller ldquoTherelationship between P-glycoprotein (PGP) polymorphismsand response to olanzapine treatment in schizophreniardquoThera-peutic Drug Monitoring vol 28 no 5 pp 668ndash672 2006

[11] H B Stolp and K M Dziegielewska ldquoReview role of devel-opmental inflammation and blood-brain barrier dysfunctionin neurodevelopmental and neurodegenerative diseasesrdquo Neu-ropathology andAppliedNeurobiology vol 35 no 2 pp 132ndash1462009

[12] D J Roberts and K B Goralski ldquoA critical overview of theinfluence of inflammation and infection on P-glycoproteinexpression and activity in the brainrdquo Expert Opinion on DrugMetabolism and Toxicology vol 4 no 10 pp 1245ndash1264 2008

[13] A L Bartels A TMWillemsen R Kortekaas et al ldquoDecreasedblood-brain barrier P-glycoprotein function in the progressionof Parkinsonrsquos disease PSP and MSArdquo Journal of Neural Trans-mission vol 115 no 7 pp 1001ndash1009 2008

[14] J van Os G Kenis and B P F Rutten ldquoThe environment andschizophreniardquo Nature vol 468 no 7321 pp 203ndash212 2010


[15] F Pharoah J J Mari J Rathbone andWWong ldquoFamily inter-vention for schizophreniardquo Cochrane Database of SystematicReviews no 4 Article ID CD000088 2006

[16] C U Nnadi and A K Malhotra ldquoIndividualizing antipsychoticdrug therapy in schizophrenia the promise of pharmacogenet-icsrdquo Current Psychiatry Reports vol 9 no 4 pp 313ndash318 2007

[17] American Psychiatric Association Diagnostic and StatisticalManual of Mental Disorders American Psychiatric AssociationWashington DC USA 4th edition 1994

[18] P Kulhara P Kulhara S Chakrabarti and S ChakrabartildquoCulture and schizophrenia and other psychotic disordersrdquoPsychiatric Clinics of North America vol 24 no 3 pp 449ndash4642001

[19] N A Khin Y-F Chen Y Yang P Yang and T P LaughrenldquoExploratory analyses of efficacy data from schizophrenia trialsin support of new drug applications submitted to the US FoodandDrugAdministrationrdquo Journal of Clinical Psychiatry vol 73no 6 pp 856ndash864 2012

[20] D G Kingdon K Ashcroft B Bhandari et al ldquoSchizophreniaand borderline personality disorder similarities and differencesin the experience of auditory hallucinations paranoia andchildhood traumardquo Journal of Nervous and Mental Disease vol198 no 6 pp 399ndash403 2010

[21] P Falkai and H-J Moller ldquoNeurobiology of schizophre-nia from outcome to pathophysiological insightsrdquo EuropeanArchives of Psychiatry and Clinical Neuroscience vol 262 no 2pp 93ndash94 2012

[22] T R Insel ldquoRethinking schizophreniardquo Nature vol 468 no7321 pp 187ndash193 2010

[23] R Tandon H A Nasrallah and M S Keshavan ldquoSchizophre-nia lsquojust the factsrsquo 4 Clinical features and conceptualizationrdquoSchizophrenia Research vol 110 no 1ndash3 pp 1ndash23 2009

[24] M Bebawy and M Chetty ldquoDifferential pharmacological reg-ulation of drug efflux and pharmacoresistant schizophreniardquoBioEssays vol 3 no 2 pp 183ndash188 2008

[25] D W Boulton C L DeVane H L Liston and J S MarkowitzldquoIn vitro P-glycoprotein affinity for atypical and conventionalantipsychoticsrdquo Life Sciences vol 71 no 2 pp 163ndash169 2002

[26] A A El Ela S Hartter U Schmitt C Hiemke H Spahn-Langguth and P Langguth ldquoIdentification of P-glycoproteinsubstrates and inhibitors among psychoactive compoundsmdashimplications for pharmacokinetics of selected substratesrdquo Jour-nal of Pharmacy and Pharmacology vol 56 no 8 pp 967ndash9752004

[27] U Schmitt A Abou El-Ela L J Guo et al ldquoCyclosporine a(CsA) affects the pharmacodynamics and pharmacokinetics ofthe atypical antipsychotic amisulpride probably via inhibitionof P-glycoprotein (P-gp)rdquo Journal of Neural Transmission vol113 no 7 pp 787ndash801 2006

[28] K S Pang ldquoModeling of intestinal drug absorption Roles oftransporters and metabolic enzymes (for the gillette reviewseries)rdquoDrugMetabolismampDisposition vol 31 no 12 pp 1507ndash1519 2003

[29] A El-Kattan and M Varma ldquoOral absorption intestinal meta-bolism and human oral bioavailabilityrdquo in Topics on DrugMeta-bolism pp 1ndash34 Pharmacokinetics Dynamics andMetabolismDepartment Pfizer New York NY USA 2012

[30] A Schlessinger N Khuri KMGiacomini andA Sali ldquoMolec-ular modeling and ligand docking for solute carrier (SLC)transportersrdquoCurrent Topics inMedicinal Chemistry vol 13 no7 pp 843ndash856 2013

[31] D Wagner H Spahn-Langguth A Hanafy A Koggel and PLangguth ldquoIntestinal drug efflux formulation and food effectsrdquoAdvancedDrugDelivery Reviews vol 50 no 1 pp S13ndashS31 2001

[32] I P Kaur R Bhandari S Bhandari and V Kakkar ldquoPotentialof solid lipid nanoparticles in brain targetingrdquo Journal ofControlled Release vol 127 no 2 pp 97ndash109 2008

[33] B T Hawkins and T P Davis ldquoThe blood-brain barrierneuro-vascular unit in health and diseaserdquo Pharmacological Reviewsvol 57 no 2 pp 173ndash185 2005

[34] W Loscher and H Potschka ldquoBlood-brain barrier active effluxtransporters ATP-binding cassette gene familyrdquo NeuroRx vol2 no 1 pp 86ndash98 2005

[35] W Loscher andH Potschka ldquoRole of drug efflux transporters inthe brain for drug disposition and treatment of brain diseasesrdquoProgress in Neurobiology vol 76 no 1 pp 22ndash76 2005

[36] G Lee S Dallas M Hong and R Bendayan ldquoDrug transport-ers in the central nervous system Brain barriers and brainparenchyma considerationsrdquo Pharmacological Reviews vol 53no 4 pp 569ndash596 2001

[37] A Misra S Ganesh A Shahiwala and S P Shah ldquoDrug deliv-ery to the central nervous system a reviewrdquo Journal of Pharmacyand Pharmaceutical Sciences vol 6 no 2 pp 252ndash273 2003

[38] J-M Scherrmann ldquoDrug delivery to brain via the blood-brainbarrierrdquo Vascular Pharmacology vol 38 no 6 pp 349ndash3542002

[39] C La FougereG BoningH Bartmann et al ldquoUptake andbind-ing of the serotonin 5-HT

1119860antagonist [18F]-MPPF in brain

of rats effects of the novel P-glycoprotein inhibitor tariquidarrdquoNeuroImage vol 49 no 2 pp 1406ndash1415 2010

[40] A H Schinkel ldquoP-Glycoprotein a gatekeeper in the blood-brain barrierrdquo Advanced Drug Delivery Reviews vol 36 no 2-3pp 179ndash194 1999

[41] S G Aller J Yu A Ward et al ldquoStructure of P-glycoproteinreveals a molecular basis for poly-specific drug bindingrdquo Sci-ence vol 323 no 5922 pp 1718ndash1722 2009

[42] D S Miller B Bauer and A M S Hartz ldquoModulation ofP-glycoprotein at the blood-brain barrier opportunities toimprove CNS pharmacotherapyrdquo Pharmacological Reviews vol60 no 2 pp 196ndash209 2008

[43] R Gabathuler ldquoApproaches to transport therapeutic drugsacross the blood-brain barrier to treat brain diseasesrdquo Neuro-biology of Disease vol 37 no 1 pp 48ndash57 2010

[44] P Matsson J M Pedersen U Norinder C A S Bergstromand P Artursson ldquoIdentification of novel specific and generalinhibitors of the three major human ATP-binding cassettetransporters P-gp BCRP and MRP2 among registered drugsrdquoPharmaceutical Research vol 26 no 8 pp 1816ndash1831 2009

[45] M V S Varma Y Ashokraj C S Dey and R PanchagnulaldquoP-glycoprotein inhibitors and their screening a perspectivefrom bioavailability enhancementrdquo Pharmacological Researchvol 48 no 4 pp 347ndash359 2003

[46] M F Rosenberg A B Kamis R Callaghan C F Higgins andR C Ford ldquoThree-dimensional structures of the mammalianmultidrug resistance P-glycoprotein demonstrate major con-formational changes in the transmembrane domains uponnucleotide bindingrdquo Journal of Biological Chemistry vol 278no 10 pp 8294ndash8299 2003

[47] N Aouali L Eddabra J Macadre and H Morjani ldquoImmuno-suppressors and reversion of multidrug-resistancerdquo CriticalReviews in OncologyHematology vol 56 no 1 pp 61ndash70 2005


[48] F J Sharom ldquoComplex interplay between the P-glycoproteinmultidrug efflux pump and the membrane Its role in modu-lating protein functionrdquo Frontiers in Oncology vol 4 Article IDArticle 41 2014

[49] O Fardel V Lecureur and A Guillouzo ldquoThe P-glycoproteinmultidrug transporterrdquo General Pharmacology The VascularSystem vol 27 no 8 pp 1283ndash1291 1996

[50] P P Constantinides andKMWasan ldquoLipid formulation strate-gies for enhancing intestinal transport and absorption of P-glycoprotein (P-gp) substrate drugs In vitroin vivo case stud-iesrdquo Journal of Pharmaceutical Sciences vol 96 no 2 pp 235ndash248 2007

[51] C F Higgins and M M Gottesman ldquoIs the multidrug trans-porter a flippaserdquo Trends in Biochemical Sciences vol 17 no 1pp 18ndash21 1992

[52] Z E Sauna M M Smith M Muller K M Kerr and S VAmbudkar ldquoThemechanism of action of multidrug-resistance-linked P-glycoproteinrdquo Journal of Bioenergetics and Biomem-branes vol 33 no 6 pp 481ndash491 2001

[53] J-S Wang H-J Zhu J L Donovan et al ldquoAripiprazole brainconcentration is altered in P-glycoprotein deficient micerdquoSchizophrenia Research vol 110 no 1-3 pp 90ndash94 2009

[54] O L de Klerk A T M Willemsen F J Bosker et al ldquoRegionalincrease in P-glycoprotein function in the blood-brain barrierof patients with chronic schizophrenia a PET study with [11C]verapamil as a probe for P-glycoprotein functionrdquo PsychiatryResearchmdashNeuroimaging vol 183 no 2 pp 151ndash156 2010

[55] J-SWang Y Ruan RM Taylor J L Donovan J SMarkowitzand C L DeVane ldquoThe brain entry of risperidone and 9-hydroxyrisperidone is greatly limited by P-glycoproteinrdquo Inter-national Journal of Neuropsychopharmacology vol 7 no 4 pp415ndash419 2004

[56] T Nakagami N Yasui-Furukori M Saito T Tateishi and SKaneo ldquoEffect of verapamil on pharmacokinetics and pharma-codynamics of risperidone in vivo evidence of involvement ofP-glycoprotein in risperidone dispositionrdquo Clinical Pharmacol-ogy andTherapeutics vol 78 no 1 pp 43ndash51 2005

[57] K M Kirschbaum S Henken C Hiemke and U SchmittldquoPharmacodynamic consequences of P-glycoprotein-depend-ent pharmacokinetics of risperidone and haloperidol in micerdquoBehavioural Brain Research vol 188 no 2 pp 298ndash303 2008

[58] B Feng J BMills R E Davidson et al ldquoIn vitro P-glycoproteinassays to predict the in vivo interactions of P-glycoprotein withdrugs in the central nervous systemrdquo Drug Metabolism andDisposition vol 36 no 2 pp 268ndash275 2008

[59] A Doran R S Obach B J Smith et al ldquoThe impact of P-glycoprotein on the disposition of drugs targeted for indicationsof the central nervous system evaluation using the MDR1A1Bknockout mouse modelrdquoDrugMetabolism and Disposition vol33 no 1 pp 165ndash174 2005

[60] S A Hitchcock ldquoStructural modifications that alter the P-glycoprotein efflux properties of compoundsrdquo Journal of Medic-inal Chemistry vol 55 no 11 pp 4877ndash4895 2012

[61] M Gohel S Modi K G Vyas and K S Rajesh ldquoDeliveryapproaches to bypass P-glycoprotein efflux pumprdquo Pharmaceu-tical Information vol 9 p 1 2011

[62] R Nieto Montesinos A Beduneau Y Pellequer and A Lam-precht ldquoDelivery of P-glycoprotein substrates using chemosen-sitizers and nanotechnology for selective and efficient therapeu-tic outcomesrdquo Journal of Controlled Release vol 161 no 1 pp50ndash61 2012

[63] E F Choo D Kurnik M Muszkat et al ldquoDifferential in vivosensitivity to inhibition of P-glycoprotein located in lympho-cytes testes and the blood-brain barrierrdquo Journal of Pharmacol-ogy and ExperimentalTherapeutics vol 317 no 3 pp 1012ndash10182006

[64] M Werle and A Bemkop-Schnurch ldquoThiolated chitosans use-ful excipients for oral drug deliveryrdquo Journal of Pharmacy andPharmacology vol 60 no 3 pp 273ndash281 2008

[65] R L Hunter JMcNicholl andA A Lal ldquoMechanisms of actionof nonionic block copolymer adjuvantsrdquo AIDS Research andHuman Retroviruses vol 10 no 2 pp 95ndash98 1994

[66] MWerle ldquoNatural and synthetic polymers as inhibitors of drugefflux pumpsrdquo Pharmaceutical Research vol 25 no 3 pp 500ndash511 2008

[67] Q Shen Y Lin T Handa et al ldquoModulation of intestinal P-glycoprotein function by polyethylene glycols and their deriva-tives by in vitro transport and in situ absorption studiesrdquo Inter-national Journal of Pharmaceutics vol 313 no 1-2 pp 49ndash562006

[68] E D Hugger K L Audus and R T Borchardt ldquoEffects ofpoly(ethylene glycol) on efflux transporter activity in Caco-2cell monolayersrdquo Journal of Pharmaceutical Sciences vol 91 no9 pp 1980ndash1990 2002

[69] B M Johnson W N Charman and C J H Porter ldquoAn invitro examination of the impact of polyethylene glycol 400pluronic p85 and vitamin E d-a-tocopheryl polyethylene glycol1000 succinate on p-glycoprotein efflux and enterocyte-basedmetabolism in excised rat intestinerdquo The AAPS Journal vol 4no 4 pp 193ndash205 2002

[70] E V Batrakova S Li S V Vinogradov V Y Alakhov D WMiller and A V Kabanov ldquoMechanism of pluronic effect on P-glycoprotein efflux system in blood brain barrier contributionsof energy depletion and membrane fluidizationrdquo Journal ofPharmacology and Experimental Therapeutics vol 299 no 2pp 483ndash493 2001

[71] E V Batrakova DWMiller S Li V Y Alakhov A V Kabanovand W F Elmquist ldquoPluronic P85 enhances the delivery ofdigoxin to the brain in vitro and in vivo studiesrdquo The Journalof Pharmacology and Experimental Therapeutics vol 296 no 2pp 551ndash557 2001

[72] J Iqbal J Hombach B Matuszczak and A Bernkop-SchnurchldquoDesign and in vitro evaluation of a novel polymeric P-glycoprotein (P-gp) inhibitorrdquo Journal of Controlled Release vol147 no 1 pp 62ndash69 2010

[73] E V Batrakova S Li Y Li V Y Alakhov and A V KabanovldquoEffect of pluronic P85 on ATPase activity of drug effluxtransportersrdquo Pharmaceutical Research vol 21 no 12 pp 2226ndash2233 2004

[74] V Saxena and M D Hussain ldquoPoloxamer 407TPGS mixedmicelles for delivery of gambogic acid to breast and multidrug-resistant cancerrdquo International Journal of Nanomedicine vol 7pp 713ndash721 2012

[75] M Werle and M Hoffer ldquoGlutathione and thiolated chitosaninhibit multidrug resistance P-glycoprotein activity in excisedsmall intestinerdquo Journal of Controlled Release vol 111 no 1-2pp 41ndash46 2006

[76] A Bernkop-SchnurchM Hornof and T Zoidl ldquoThiolated pol-ymersmdashthiomers synthesis and in vitro evaluation of chitosan-2-iminothiolane conjugatesrdquo International Journal of Pharma-ceutics vol 260 no 2 pp 229ndash237 2003


[77] T Bansal N Akhtar M Jaggi R K Khar and S TalegaonkarldquoNovel formulation approaches for optimising delivery of anti-cancer drugs based on P-glycoprotein modulationrdquo Drug Dis-covery Today vol 14 no 21-22 pp 1067ndash1074 2009

[78] B D Rege J P Y Kao and J E Polli ldquoEffects of nonionic sur-factants on membrane transporters in Caco-2 cell monolayersrdquoEuropean Journal of Pharmaceutical Sciences vol 16 no 4-5 pp237ndash246 2002

[79] X Huo Q Liu C Wang et al ldquoEnhancement effect of P-gp inhibitors on the intestinal absorption and antiproliferativeactivity of bestatinrdquo European Journal of Pharmaceutical Sci-ences vol 50 no 3-4 pp 420ndash428 2013

[80] M Li L Si H Pan et al ldquoExcipients enhance intestinal absorp-tion of ganciclovir by P-gp inhibition assessed in vitro byeverted gut sac and in situ by improved intestinal perfusionrdquoInternational Journal of Pharmaceutics vol 403 no 1-2 pp 37ndash45 2011

[81] J S Woo C H Lee C K Shim and S-J Hwang ldquoEnhancedoral bioavailability of paclitaxel by coadministration of the p-glycoprotein inhibitor KR30031rdquo Pharmaceutical Research vol20 no 1 pp 24ndash30 2003

[82] A M Al-Mohizea ldquoInfluence of intestinal efflux pumps on theabsorption and transport of furosemiderdquo Saudi PharmaceuticalJournal vol 18 no 2 pp 97ndash101 2010

[83] H L Wong X Y Wu and R Bendayan ldquoNanotechnologicaladvances for the delivery of CNS therapeuticsrdquo Advanced DrugDelivery Reviews vol 64 no 7 pp 686ndash700 2012

[84] A Agarwal N Lariya G Saraogi N Dubey H Agrawal andGP Agrawal ldquoNanoparticles as novel carrier for brain delivery areviewrdquo Current Pharmaceutical Design vol 15 no 8 pp 917ndash925 2009

[85] M D Chavanpatil A Khdair B Gerard et al ldquoSurfactant-pol-ymer nanoparticles overcome P-glycoprotein-mediated drugeffluxrdquoMolecular Pharmaceutics vol 4 no 5 pp 730ndash738 2007

[86] A Fortuna G Alves and A Falcao ldquoIn vitro and in vivorelevance of the p-glycoprotein probe substrates in drug dis-covery and development focus on rhodamine 123 digoxin andtalinololrdquo Journal of Bioequivalence amp Bioavailability vol 1 no2 2011

[87] B Mandal H Bhattacharjee N Mittal et al ldquoCore-shell-typelipid-polymer hybrid nanoparticles as a drug delivery platformrdquoNanomedicine Nanotechnology Biology and Medicine vol 9no 4 pp 474ndash491 2013

[88] A Lamprecht and J-P Benoit ldquoEtoposide nanocarriers sup-press glioma cell growth by intracellular drug delivery andsimultaneous P-glycoprotein inhibitionrdquo Journal of ControlledRelease vol 112 no 2 pp 208ndash213 2006

[89] E Roger F Lagarce E Garcion and J-P Benoit ldquoReciprocalcompetition between lipid nanocapsules and P-gp for paclitaxeltransport across Caco-2 cellsrdquo European Journal of Pharmaceu-tical Sciences vol 40 no 5 pp 422ndash429 2010

[90] C W Gan and S-S Feng ldquoTransferrin-conjugated nanoparti-cles of Poly(lactide)-d-120572-Tocopheryl polyethylene glycol succi-nate diblock copolymer for targeted drug delivery across theblood-brain barrierrdquoBiomaterials vol 31 no 30 pp 7748ndash77572010

[91] F Wang D Zhang Q Zhang et al ldquoSynergistic effect of folate-mediated targeting and verapamil-mediated P-gp inhibitionwith paclitaxel-polymer micelles to overcome multi-drug resis-tancerdquo Biomaterials vol 32 no 35 pp 9444ndash9456 2011

[92] S Danson D Ferry V Alakhov et al ldquoPhase I dose escalationand pharmacokinetic study of pluronic polymer-bound dox-orubicin (SP1049C) in patients with advanced cancerrdquo BritishJournal of Cancer vol 90 no 11 pp 2085ndash2091 2004

[93] A Beduneau P Saulnier N Anton et al ldquoPegylated nanocap-sules produced by an organic solvent-freemethod evaluation oftheir stealth propertiesrdquo Pharmaceutical Research vol 23 no 9pp 2190ndash2199 2006

[94] J Huwyler A Cerletti G Fricker A N Eberle and J DreweldquoBy-passing of P-glycoprotein using immunoliposomesrdquo Jour-nal of Drug Targeting vol 10 no 1 pp 73ndash79 2002

[95] R Krishna N McIntosh K W Riggs and L D Mayer ldquoDox-orubicin encapsulated in sterically stabilized liposomes exhibitsrenal and biliary clearance properties that are independent ofvalspodar (PSC 833) under conditions that significantly inhibitnonencapsulated drug excretionrdquo Clinical Cancer Research vol5 no 10 pp 2939ndash2947 1999

[96] K D Lee K Hong and D Papahadjopoulos ldquoRecognition ofliposomes by cells In vitro binding and endocytosis medi-ated by specific lipid headgroups and surface charge densityrdquoBiochimica et Biophysica ActamdashBiomembranes vol 1103 no 2pp 185ndash197 1992

[97] E R Gillies and J M J Frechet ldquoDendrimers and dendriticpolymers in drug deliveryrdquo Drug Discovery Today vol 10 no1 pp 35ndash43 2005

[98] D Cui Q Xu S Gu J Shi and X Che ldquoPAMAM-drug com-plex for delivering anticancer drug across blood-brain barrierin-vitro and in-vivordquoAfrican Journal of Pharmacy and Pharma-cology vol 3 no 5 pp 227ndash233 2009

[99] A DrsquoEmanuele R Jevprasesphant J Penny and D AttwoodldquoThe use of a dendrimer-propranolol prodrug to bypass effluxtransporters and enhance oral bioavailabilityrdquo Journal of Con-trolled Release vol 95 no 3 pp 447ndash453 2004

[100] S Svenson ldquoDendrimers as versatile platform in drug deliveryapplicationsrdquo European Journal of Pharmaceutics and Biophar-maceutics vol 71 no 3 pp 445ndash462 2009

[101] M SMuthu and S Singh ldquoPoly (D L-lactide) nanosuspensionsof risperidone for parenteral delivery formulation and in-vitroevaluationrdquoCurrent DrugDelivery vol 6 no 1 pp 62ndash68 2009

[102] R van der Meel M H A M Fens P Vader W W van SolingeO Eniola-Adefeso and R M Schiffelers ldquoExtracellular vesiclesas drug delivery systems lessons from the liposome fieldrdquoJournal of Controlled Release vol 195 pp 72ndash85 2014

[103] S M van Dommelen P Vader S Lakhal et al ldquoMicrovesiclesand exosomes opportunities for cell-derived membrane vesi-cles in drug deliveryrdquo Journal of Controlled Release vol 161 no2 pp 635ndash644 2012

[104] M J Haney N L Klyachko Y Zhao et al ldquoExosomes as drugdelivery vehicles for Parkinsonrsquos disease therapyrdquo Journal ofControlled Release vol 207 pp 18ndash30 2015

[105] K M Mahar Doan J E Humphreys L O Webster et al ldquoPas-sive permeability and P-glycoprotein-mediated efflux differen-tiate central nervous system (CNS) and non-CNS marketeddrugsrdquo The Journal of Pharmacology and Experimental Thera-peutics vol 303 no 3 pp 1029ndash1037 2002

[106] H L Wong R Bendayan A M Rauth and X Y Wu ldquoSimul-taneous delivery of doxorubicin and GG918 (Elacridar) by newpolymer-lipid hybrid nanoparticles (PLN) for enhanced treat-ment ofmultidrug-resistant breast cancerrdquo Journal of ControlledRelease vol 116 no 3 pp 275ndash284 2006


[107] A Beloqui M A Solinıs A R Gascon A Del Pozo-Rodrıguez ADes Rieux andV Preat ldquoMechanismof transportof saquinavir-loaded nanostructured lipid carriers across theintestinal barrierrdquo Journal of Controlled Release vol 166 no 2pp 115ndash123 2013

[108] Y-C Kuo and H-H Chen ldquoEffect of nanoparticulate polybu-tylcyanoacrylate and methylmethacrylate-sulfopropylmetha-crylate on the permeability of zidovudine and lamivudineacross the in vitro blood-brain barrierrdquo International Journal ofPharmaceutics vol 327 no 1-2 pp 160ndash169 2006

[109] M M Yallapu M Jaggi and S C Chauhan ldquoDesign andengineering of nanogels for cancer treatmentrdquo Drug DiscoveryToday vol 16 no 9-10 pp 457ndash463 2011

[110] N Nasongkla E Bey J Ren et al ldquo Multifunctional polymericmicelles as cancer-targeted MRI-ultrasensitive drug deliverysystemsrdquo Nano Letters vol 6 pp 2427ndash2430 2006

[111] R Mo X Jin N Li et al ldquoThe mechanism of enhancement onoral absorption of paclitaxel by N-octyl-O-sulfate chitosanmicellesrdquo Biomaterials vol 32 no 20 pp 4609ndash4620 2011

[112] S-H Kim and C-C Chu ldquoSynthesis and characterization ofdextran-methacrylate hydrogels and structural study by SEMrdquoJournal of Biomedical Materials Research vol 49 no 4 pp 517ndash527 2000

[113] X Zhuang X Tian Y Zheng et al ldquoFormulation and physic-ochemical characterisation of a novel self-microemulsifyingdelivery system as hydrotropic and solubilising agent for pen-fluridolrdquo Procedia Engineering vol 18 pp 59ndash65 2011 Proceed-ings of the 2nd SREE Conference on Chemical Engineering(CCE rsquo11)

[114] L M Negi M Tariq and S Talegaonkar ldquoNano scale self-emulsifying oil based carrier system for improved oral bioavail-ability of camptothecin derivative by P-Glycoprotein modula-tionrdquoColloids and Surfaces B Biointerfaces vol 111 pp 346ndash3532013

[115] M Estudante J G Morais G Soveral and L Z Benet ldquoIntesti-nal drug transporters an overviewrdquo Advanced Drug DeliveryReviews vol 65 no 10 pp 1340ndash1356 2013

[116] P Blasi S Giovagnoli A Schoubben M Ricci and C RossildquoSolid lipid nanoparticles for targeted brain drug deliveryrdquoAdvanced Drug Delivery Reviews vol 59 no 6 pp 454ndash4772007

[117] R Kumar andV R Sinha ldquoThiomer a potential carrier for ther-apeutic deliveryrdquo Reactive amp Functional Polymers vol 73 no 8pp 1156ndash1166 2013


into the brain (iii) metabolic stability of the drug and(iv) the active transport out of the intestine and brainendothelium via efflux pump transporters There are threeclasses of transporters that have been associated with theefflux of drugs-monocarboxylic acid transporters organicion transporters and multidrug resistance transporters Thisremarkable system of transporters provides a viable mecha-nism through which the permeation of CNS targeted drugsinto the brain is effectually decreased The action of theseefflux transporters at the level of the intestine and BBBmay bedemonstrated clinically as the reduced effectiveness of drugtherapy targeted at CNS disorders [5]

In addition various multispecific transport proteins havealso been identified within the intestine and BBB Some ofthese belong to the ATP-binding cassette (ABC) superfamilyof transporters with P-glycoprotein (P-gp) multidrug resis-tance associated protein (MRP) and breast cancer resistanceprotein (BCRP) as representative examples [4 6] P-gp isa membrane transporter of the ABC superfamily locatedwithin both the intestinal epithelium and the BBB thusplaying a dynamic role in the bioavailability of orally adminis-tered drugs employed in the treatment of neurodegenerativedisorders [7] We propose that drug molecules intended forthe treatment of CNS disorders must be capable of bypassingthe P-gp efflux pump at the intestinal and BBB levels so as toattain effective brain concentrations

Regardless of the vast advances in brain research out-puts neurodegenerative and psychiatric disorders remain theworldrsquos leading causes of disability morbidity and mortality[8] Dysfunctions in the P-gp efflux transporter have alreadybeen suggested to play a role in the development of neu-rodegenerative disorders such as Parkinsonrsquos andAlzheimerrsquosdiseases Genetic variations in theMDR1 gene associatedwithreduced P-gp function at the BBB have been related to ahigher risk of Parkinsonrsquos diseaseThe reduced function of theP-gp efflux pump has been noted in most neurodegenerativedisorders It has been hypothesized that the decreased P-gpfunction in the BBBmay increase the risk and hence the inci-dence of neurological diseases [9] In schizophrenia geneticvariations of the ABCB1 (ATP-binding cassette subfamilyB) gene also known as the MDR1 (multidrug resistance)gene have been described as the predisposing factors forschizophrenia and other neurodegenerative diseases Theyhave also been employed as determinants of treatmentresponse to antipsychotics [10] As in other neurodegener-ative diseases the BBB maybe compromised by way of theinflammatory and neurodegenerative processes [11] hencethe functionality of P-gp is influenced by the inflammatoryresponses [12] As discussed previously there exists a reduc-tion of P-gp function in progression of neurodegenerativediseases Conversely there is evidence of increased P-gpfunction in patients presenting with schizophrenia [13]

Schizophrenia is a neurodegenerative disorder that isknown to affect approximately 1 of the worldrsquos population[14] with a further 25 of patients approximated to beafflicted by the disease experiencing nonremitting sickness[15] The disorder is characterized by disturbances of per-ception thought and volition with significant impairmentin social and occupational functioning Studies have shown

that roughly 10 of schizophrenic patients commit suicideA recent study showed that more than 70 of patientsdiagnosed with chronic schizophrenia discontinued theirantipsychotic drug therapy due to poor effectiveness ortolerability [16ndash22]

Schizophrenia is clinically characterized by the incidenceof symptoms such as hallucinations and delusions which arecollectively termed ldquopositiverdquo symptoms whereas symptomspertaining to expression of emotional dullness and socialwithdrawal are recognized as ldquonegativerdquo symptoms [15]Figure 1(a) diagrammatically depicts the symptom cascade

Schizophrenia is widely characterized via a successivecourse that involves three distinct phases namely phase1 (premorbid) defined by cognitive motor and societaldysfunction phase 2 (prodromal) which is characterized byweakened positive symptoms and accompanying deteriorat-ing functionality and phase 3 (plateau) in which the positivepsychosis defining symptoms are less conspicuous and thenegative symptoms including cognitive deficits are generallypredominant [23] Figure 1(b) illustrates the clinical stages ofschizophrenia progression

It has been discovered that ldquopharmacoresistant schizo-phreniardquo is a noteworthy obstacle to the successful manage-ment of the disease within the clinical settingThe prevalenceof pharmacoresistant schizophrenia is understood to beapproximately 129 to 48 of all schizophrenic patients andpersists regardless of the use of drug combination treatmentregimens with possible therapeutic efficacy Majority ofpatients presenting with treatment resistant schizophreniaare on atypical antipsychoticmedication Recent in vitro stud-ies have shown that drugs such as amisulpride risperidonequetiapine and clozapine have a varying degree of affinityfor the P-gp efflux transporter [24ndash26] An additional studywas conducted to determine the effect that cyclosporine Aa P-gp inhibitor has on the brain uptake of amisulpride (arecognized P-gp substrate) In vitro and in vivo results dis-played that amisulpride when coadministered with 50mgkgof cyclosporine A showed an increase and prolonged antipsy-chotic effect The area under the curve (AUC) in serum andthe brain was increased in cyclosporine cotreated rats Thesedata points indicated a pharmacokinetic interaction betweencyclosporine A and amisulpride which is most likely dueto P-gp inhibition [27] Thus the expression and functionof the P-gp efflux transporter have been recently impli-cated in the occurrence of pharmacoresistant schizophreniaAntipsychotic drugs have also been shown to stimulate thecatalytic activity of P-gp providing additional evidence ofthe participation of P-gp-mediated drug extrusion processesin restraining CNS penetration of these drugs It has beensuggested that some of the principles observed with thecombination treatment of P-gp-mediated drug resistance incancer may be applied to elucidate the involvement of P-gp indrug-resistant schizophrenia There exists a greatly emergentbody of evidence supporting the role of P-gp on the effluxof antipsychotic agents from the BBB however limitedconsideration has been focused on the modulation of P-gpfunction by polymeric materials excipients and drug deliv-ery systems used in other P-gpmodulated treatment-resistantdisease states [24]






gtMengtWomen


Sever

itySeverity

Affective

Psychosis Negative

Cognitive

Heritability



sim40 sim40

sim40ndash70

sim80ndash90


health

care fi

lter

Mental health

care filterHelp


Socialconflict

competence

G times E

(a)



Stage 4




Stage 3


pursuing

Stage 2



dysfunction

Stage 1

(ii) Help

(b)










P-gp

MRP2

MRP1

MRP3

MRP4

MRP5

MCT1

OCT1

OCT2

BloodEnterocyte

Apical

Intestinallumen

Junctionalcomplex

Basolateral

OATPs

BCRP

PEPTOCTNs

PMAT








Astrocyte

Basement membrane


Pericyte

Endothelial cell

Blood

Lymphocyte

Monocyte

Neutrophil

Blood-brainbarrier

Brain Microglia

Astrocyte

Tight junction

Endothelial cell

Basementmembrane









997888997888997888997888997888997888997888997888997888997888997888997888997888997888997888rarr



MRP1

MRP2

MRP3

MRP4

MRP6MRP5

P-gp BCRP

Apicalluminal

Basolateral

Blood

Brain


Tightjunction




times 100 (1)








CytosolP-gp

COOH

COOH

COOH

MRP1

TM TM

TM

NBD NBD

NBD

TMD0

L0

NH2

NH2

NH2

BCRP

(a)

Outer surface


Flippase model

(b)












2and

















Moderate [59 105]


Low [59 105]






















Natural polymers



[65]

Synthetic polymers



[65 66]

Pluronic P85


[66 68 69]

Thiomers


[71]








Nonthiolatedpolymer

Thiolatedpolymer



Mucousmembrane






























50values


100nm

5nm



















Endosomalrelease


P-gp P-gp

(A) (B)

(a)

(A) (B)

Core

Branchingpoints

Surfacegroups

Molecularcargo

123 z

zz

zzzzzz

zzz

zz z z z z z

zz

zz

z

G3 asymp 50nm

(b)






Table4

Drugdeliverysyste

mPo

lymer

Drug

Application

References

Nanocarrie

r(nanosph

eres)

Polyethylene

glycol

Polybu

tylcyano

acrylatealginate

polyethylene

glycolpolylactic

ndashco-

glycolicacidand

polylacticacid

Doxorub

icinclozapinem

etho

trexate

saqu

inavir

andzido

vudine

Drugmoleculeisd

elivered

tothec

ell

nucle

usandthus

avoids

recogn

ition

bythe


uxpu

mp

[83106ndash

108]

Lipo

somes

Phosph

olipidsa

ndcholesterol

Epiru

bicin

cisplatinm

etho

trexate

anddo

xorubicin

ItinhibitsP-gp

efflux

transporterb

yinteractionwith

phosph

olipidsthes

ystem

may

also

incorporateP

-gpinhibitors

[9596]

Polymer

nano

particles

Acrylic

polymerssuchas

poly-butyl-cyano

acrylate(PBC

A)

Loperamidea

nddo

xorubicin

Itbypasses

theP

-gpdu

eititsnano

size

[106]

Dendrim

ers

Manno

sylatedpo

ly(propyleneim

ine)

andpo

lyethylene

glycol-poly(am

idoamine)

Vinb

lastinedo

xorubicin

and

prop

rano

lol(intestinal)

ItinhibitsP-gp

efflux

bybypassingthep

ump

[97ndash99]

Nanogels

Catio

nica

ndno

n-ionicp

olym

ers

NVPNIPAM

Antise

nsep

hospho

rothioate

oligon

ucleotides

(SODN)a

nd5-flu

orou

racil

Itallowsfor

theincorpo

ratio

nof

P-gp

inhibitors

Polysorbatec

oatin

gof

nano

gelincreases


m018

to052

[83109]

Micelles

Pluron

icsL

61andF127

andP8

5Doxorub


riton

avir

andvinb

lastine

(1)Itinh

ibits

P-gp

efflux

andalso

involves

intracellulard

rugtransportm

odificatio

ntherebyavoiding

theP

-gpeffl

uxpu

mp

(2)D

rugperm

eabilityin

mon

olayered

BBB

mod

elby

P-gp

substrates

increasedfro

m16

-to

29-fo

ldN

ochange

indigoxin

concentrationin

mdr1k

nockou

tmice

[83110

111]

Hydrogels

(hydroxyprop

yl)M

ethacrylam

ide

Cyclo

sporineA

anddo

xorubicin

ItinhibitstheP

-gpeffl

uxtransporterb

yincorporationof

drugssuchas

cyclo

sporine

AthatareP

-gpinhibitors

[112]

LipidNanocapsule

PEG-H

S(polyethyleneg

lycol-6


polymersandHPM

CEtop

osidea

ndtacrolim

us(1)Itinh

ibits

P-gp

efflux

byincorporationof

surfa

ctantb

ased

P-gp

inhibitors

[8389]

Triglycerid

esof

capricandcaprylic

acidsSolutol

Paclitaxel

(2)P

aclitaxelup

take

increasedin

MDR1

expressin

gcellsthe

half-lifeinbrain

prolon

gedfro

m21min

togt5h

Self-em

ulsifying

drug

deliverysyste

ms

Poly-m

ethacrylatep

olym

ers

Paclitaxeland

yacrolim

usItinhibitsP-gp

efflux

byincorporationof

surfa

ctantb

ased

P-gp

inhibitorsfor

exam

pleTw

een

[113114]

Medium

chaintriglycerid

ePE

G40

0po

lysorbate8

0andcrem

opho

rEL

Penfl

uridol(schizop

hreniatherapeutic

agent)

Itenhances

solubilizationof

drug

andthus

effectiv

ebrain

concentrations

Capm

ulMCM

-C8crem

opho

rELand

pluron

icL-121

Irinotecan


P-gp

mod

ulation

Nanosuspension

Pluron

icF6

8Risperidon

eP-gp

efflux

inhibitio

nby

employing

polymersthatinh

ibittheP

-gptransporter

such

aspluron

ic

[101]




10 Conclusions




References

































































































































gtMengtWomen


Sever

itySeverity

Affective

Psychosis Negative

Cognitive

Heritability



sim40 sim40

sim40ndash70

sim80ndash90


health

care fi

lter

Mental health

care filterHelp


Socialconflict

competence

G times E

(a)



Stage 4




Stage 3


pursuing

Stage 2



dysfunction

Stage 1

(ii) Help

(b)










P-gp

MRP2

MRP1

MRP3

MRP4

MRP5

MCT1

OCT1

OCT2

BloodEnterocyte

Apical

Intestinallumen

Junctionalcomplex

Basolateral

OATPs

BCRP

PEPTOCTNs

PMAT








Astrocyte

Basement membrane


Pericyte

Endothelial cell

Blood

Lymphocyte

Monocyte

Neutrophil

Blood-brainbarrier

Brain Microglia

Astrocyte

Tight junction

Endothelial cell

Basementmembrane









997888997888997888997888997888997888997888997888997888997888997888997888997888997888997888rarr



MRP1

MRP2

MRP3

MRP4

MRP6MRP5

P-gp BCRP

Apicalluminal

Basolateral

Blood

Brain


Tightjunction




times 100 (1)








CytosolP-gp

COOH

COOH

COOH

MRP1

TM TM

TM

NBD NBD

NBD

TMD0

L0

NH2

NH2

NH2

BCRP

(a)

Outer surface


Flippase model

(b)












2and

















Moderate [59 105]


Low [59 105]






















Natural polymers



[65]

Synthetic polymers



[65 66]

Pluronic P85


[66 68 69]

Thiomers


[71]








Nonthiolatedpolymer

Thiolatedpolymer



Mucousmembrane






























50values


100nm

5nm



















Endosomalrelease


P-gp P-gp

(A) (B)

(a)

(A) (B)

Core

Branchingpoints

Surfacegroups

Molecularcargo

123 z

zz

zzzzzz

zzz

zz z z z z z

zz

zz

z

G3 asymp 50nm

(b)






Table4

Drugdeliverysyste

mPo

lymer

Drug

Application

References

Nanocarrie

r(nanosph

eres)

Polyethylene

glycol

Polybu

tylcyano

acrylatealginate

polyethylene

glycolpolylactic

ndashco-

glycolicacidand

polylacticacid

Doxorub

icinclozapinem

etho

trexate

saqu

inavir

andzido

vudine

Drugmoleculeisd

elivered

tothec

ell

nucle

usandthus

avoids

recogn

ition

bythe


uxpu

mp

[83106ndash

108]

Lipo

somes

Phosph

olipidsa

ndcholesterol

Epiru

bicin

cisplatinm

etho

trexate

anddo

xorubicin

ItinhibitsP-gp

efflux

transporterb

yinteractionwith

phosph

olipidsthes

ystem

may

also

incorporateP

-gpinhibitors

[9596]

Polymer

nano

particles

Acrylic

polymerssuchas

poly-butyl-cyano

acrylate(PBC

A)

Loperamidea

nddo

xorubicin

Itbypasses

theP

-gpdu

eititsnano

size

[106]

Dendrim

ers

Manno

sylatedpo

ly(propyleneim

ine)

andpo

lyethylene

glycol-poly(am

idoamine)

Vinb

lastinedo

xorubicin

and

prop

rano

lol(intestinal)

ItinhibitsP-gp

efflux

bybypassingthep

ump

[97ndash99]

Nanogels

Catio

nica

ndno

n-ionicp

olym

ers

NVPNIPAM

Antise

nsep

hospho

rothioate

oligon

ucleotides

(SODN)a

nd5-flu

orou

racil

Itallowsfor

theincorpo

ratio

nof

P-gp

inhibitors

Polysorbatec

oatin

gof

nano

gelincreases


m018

to052

[83109]

Micelles

Pluron

icsL

61andF127

andP8

5Doxorub


riton

avir

andvinb

lastine

(1)Itinh

ibits

P-gp

efflux

andalso

involves

intracellulard

rugtransportm

odificatio

ntherebyavoiding

theP

-gpeffl

uxpu

mp

(2)D

rugperm

eabilityin

mon

olayered

BBB

mod

elby

P-gp

substrates

increasedfro

m16

-to

29-fo

ldN

ochange

indigoxin

concentrationin

mdr1k

nockou

tmice

[83110

111]

Hydrogels

(hydroxyprop

yl)M

ethacrylam

ide

Cyclo

sporineA

anddo

xorubicin

ItinhibitstheP

-gpeffl

uxtransporterb

yincorporationof

drugssuchas

cyclo

sporine

AthatareP

-gpinhibitors

[112]

LipidNanocapsule

PEG-H

S(polyethyleneg

lycol-6


polymersandHPM

CEtop

osidea

ndtacrolim

us(1)Itinh

ibits

P-gp

efflux

byincorporationof

surfa

ctantb

ased

P-gp

inhibitors

[8389]

Triglycerid

esof

capricandcaprylic

acidsSolutol

Paclitaxel

(2)P

aclitaxelup

take

increasedin

MDR1

expressin

gcellsthe

half-lifeinbrain

prolon

gedfro

m21min

togt5h

Self-em

ulsifying

drug

deliverysyste

ms

Poly-m

ethacrylatep

olym

ers

Paclitaxeland

yacrolim

usItinhibitsP-gp

efflux

byincorporationof

surfa

ctantb

ased

P-gp

inhibitorsfor

exam

pleTw

een

[113114]

Medium

chaintriglycerid

ePE

G40

0po

lysorbate8

0andcrem

opho

rEL

Penfl

uridol(schizop

hreniatherapeutic

agent)

Itenhances

solubilizationof

drug

andthus

effectiv

ebrain

concentrations

Capm

ulMCM

-C8crem

opho

rELand

pluron

icL-121

Irinotecan


P-gp

mod

ulation

Nanosuspension

Pluron

icF6

8Risperidon

eP-gp

efflux

inhibitio

nby

employing

polymersthatinh

ibittheP

-gptransporter

such

aspluron

ic

[101]




10 Conclusions




References
































































































































P-gp

MRP2

MRP1

MRP3

MRP4

MRP5

MCT1

OCT1

OCT2

BloodEnterocyte

Apical

Intestinallumen

Junctionalcomplex

Basolateral

OATPs

BCRP

PEPTOCTNs

PMAT








Astrocyte

Basement membrane


Pericyte

Endothelial cell

Blood

Lymphocyte

Monocyte

Neutrophil

Blood-brainbarrier

Brain Microglia

Astrocyte

Tight junction

Endothelial cell

Basementmembrane









997888997888997888997888997888997888997888997888997888997888997888997888997888997888997888rarr



MRP1

MRP2

MRP3

MRP4

MRP6MRP5

P-gp BCRP

Apicalluminal

Basolateral

Blood

Brain


Tightjunction




times 100 (1)








CytosolP-gp

COOH

COOH

COOH

MRP1

TM TM

TM

NBD NBD

NBD

TMD0

L0

NH2

NH2

NH2

BCRP

(a)

Outer surface


Flippase model

(b)












2and

















Moderate [59 105]


Low [59 105]






















Natural polymers



[65]

Synthetic polymers



[65 66]

Pluronic P85


[66 68 69]

Thiomers


[71]








Nonthiolatedpolymer

Thiolatedpolymer



Mucousmembrane






























50values


100nm

5nm



















Endosomalrelease


P-gp P-gp

(A) (B)

(a)

(A) (B)

Core

Branchingpoints

Surfacegroups

Molecularcargo

123 z

zz

zzzzzz

zzz

zz z z z z z

zz

zz

z

G3 asymp 50nm

(b)






Table4

Drugdeliverysyste

mPo

lymer

Drug

Application

References

Nanocarrie

r(nanosph

eres)

Polyethylene

glycol

Polybu

tylcyano

acrylatealginate

polyethylene

glycolpolylactic

ndashco-

glycolicacidand

polylacticacid

Doxorub

icinclozapinem

etho

trexate

saqu

inavir

andzido

vudine

Drugmoleculeisd

elivered

tothec

ell

nucle

usandthus

avoids

recogn

ition

bythe


uxpu

mp

[83106ndash

108]

Lipo

somes

Phosph

olipidsa

ndcholesterol

Epiru

bicin

cisplatinm

etho

trexate

anddo

xorubicin

ItinhibitsP-gp

efflux

transporterb

yinteractionwith

phosph

olipidsthes

ystem

may

also

incorporateP

-gpinhibitors

[9596]

Polymer

nano

particles

Acrylic

polymerssuchas

poly-butyl-cyano

acrylate(PBC

A)

Loperamidea

nddo

xorubicin

Itbypasses

theP

-gpdu

eititsnano

size

[106]

Dendrim

ers

Manno

sylatedpo

ly(propyleneim

ine)

andpo

lyethylene

glycol-poly(am

idoamine)

Vinb

lastinedo

xorubicin

and

prop

rano

lol(intestinal)

ItinhibitsP-gp

efflux

bybypassingthep

ump

[97ndash99]

Nanogels

Catio

nica

ndno

n-ionicp

olym

ers

NVPNIPAM

Antise

nsep

hospho

rothioate

oligon

ucleotides

(SODN)a

nd5-flu

orou

racil

Itallowsfor

theincorpo

ratio

nof

P-gp

inhibitors

Polysorbatec

oatin

gof

nano

gelincreases


m018

to052

[83109]

Micelles

Pluron

icsL

61andF127

andP8

5Doxorub


riton

avir

andvinb

lastine

(1)Itinh

ibits

P-gp

efflux

andalso

involves

intracellulard

rugtransportm

odificatio

ntherebyavoiding

theP

-gpeffl

uxpu

mp

(2)D

rugperm

eabilityin

mon

olayered

BBB

mod

elby

P-gp

substrates

increasedfro

m16

-to

29-fo

ldN

ochange

indigoxin

concentrationin

mdr1k

nockou

tmice

[83110

111]

Hydrogels

(hydroxyprop

yl)M

ethacrylam

ide

Cyclo

sporineA

anddo

xorubicin

ItinhibitstheP

-gpeffl

uxtransporterb

yincorporationof

drugssuchas

cyclo

sporine

AthatareP

-gpinhibitors

[112]

LipidNanocapsule

PEG-H

S(polyethyleneg

lycol-6


polymersandHPM

CEtop

osidea

ndtacrolim

us(1)Itinh

ibits

P-gp

efflux

byincorporationof

surfa

ctantb

ased

P-gp

inhibitors

[8389]

Triglycerid

esof

capricandcaprylic

acidsSolutol

Paclitaxel

(2)P

aclitaxelup

take

increasedin

MDR1

expressin

gcellsthe

half-lifeinbrain

prolon

gedfro

m21min

togt5h

Self-em

ulsifying

drug

deliverysyste

ms

Poly-m

ethacrylatep

olym

ers

Paclitaxeland

yacrolim

usItinhibitsP-gp

efflux

byincorporationof

surfa

ctantb

ased

P-gp

inhibitorsfor

exam

pleTw

een

[113114]

Medium

chaintriglycerid

ePE

G40

0po

lysorbate8

0andcrem

opho

rEL

Penfl

uridol(schizop

hreniatherapeutic

agent)

Itenhances

solubilizationof

drug

andthus

effectiv

ebrain

concentrations

Capm

ulMCM

-C8crem

opho

rELand

pluron

icL-121

Irinotecan


P-gp

mod

ulation

Nanosuspension

Pluron

icF6

8Risperidon

eP-gp

efflux

inhibitio

nby

employing

polymersthatinh

ibittheP

-gptransporter

such

aspluron

ic

[101]




10 Conclusions




References






























































































































Astrocyte

Basement membrane


Pericyte

Endothelial cell

Blood

Lymphocyte

Monocyte

Neutrophil

Blood-brainbarrier

Brain Microglia

Astrocyte

Tight junction

Endothelial cell

Basementmembrane









997888997888997888997888997888997888997888997888997888997888997888997888997888997888997888rarr



MRP1

MRP2

MRP3

MRP4

MRP6MRP5

P-gp BCRP

Apicalluminal

Basolateral

Blood

Brain


Tightjunction




times 100 (1)








CytosolP-gp

COOH

COOH

COOH

MRP1

TM TM

TM

NBD NBD

NBD

TMD0

L0

NH2

NH2

NH2

BCRP

(a)

Outer surface


Flippase model

(b)












2and

















Moderate [59 105]


Low [59 105]






















Natural polymers



[65]

Synthetic polymers



[65 66]

Pluronic P85


[66 68 69]

Thiomers


[71]








Nonthiolatedpolymer

Thiolatedpolymer



Mucousmembrane






























50values


100nm

5nm



















Endosomalrelease


P-gp P-gp

(A) (B)

(a)

(A) (B)

Core

Branchingpoints

Surfacegroups

Molecularcargo

123 z

zz

zzzzzz

zzz

zz z z z z z

zz

zz

z

G3 asymp 50nm

(b)






Table4

Drugdeliverysyste

mPo

lymer

Drug

Application

References

Nanocarrie

r(nanosph

eres)

Polyethylene

glycol

Polybu

tylcyano

acrylatealginate

polyethylene

glycolpolylactic

ndashco-

glycolicacidand

polylacticacid

Doxorub

icinclozapinem

etho

trexate

saqu

inavir

andzido

vudine

Drugmoleculeisd

elivered

tothec

ell

nucle

usandthus

avoids

recogn

ition

bythe


uxpu

mp

[83106ndash

108]

Lipo

somes

Phosph

olipidsa

ndcholesterol

Epiru

bicin

cisplatinm

etho

trexate

anddo

xorubicin

ItinhibitsP-gp

efflux

transporterb

yinteractionwith

phosph

olipidsthes

ystem

may

also

incorporateP

-gpinhibitors

[9596]

Polymer

nano

particles

Acrylic

polymerssuchas

poly-butyl-cyano

acrylate(PBC

A)

Loperamidea

nddo

xorubicin

Itbypasses

theP

-gpdu

eititsnano

size

[106]

Dendrim

ers

Manno

sylatedpo

ly(propyleneim

ine)

andpo

lyethylene

glycol-poly(am

idoamine)

Vinb

lastinedo

xorubicin

and

prop

rano

lol(intestinal)

ItinhibitsP-gp

efflux

bybypassingthep

ump

[97ndash99]

Nanogels

Catio

nica

ndno

n-ionicp

olym

ers

NVPNIPAM

Antise

nsep

hospho

rothioate

oligon

ucleotides

(SODN)a

nd5-flu

orou

racil

Itallowsfor

theincorpo

ratio

nof

P-gp

inhibitors

Polysorbatec

oatin

gof

nano

gelincreases


m018

to052

[83109]

Micelles

Pluron

icsL

61andF127

andP8

5Doxorub


riton

avir

andvinb

lastine

(1)Itinh

ibits

P-gp

efflux

andalso

involves

intracellulard

rugtransportm

odificatio

ntherebyavoiding

theP

-gpeffl

uxpu

mp

(2)D

rugperm

eabilityin

mon

olayered

BBB

mod

elby

P-gp

substrates

increasedfro

m16

-to

29-fo

ldN

ochange

indigoxin

concentrationin

mdr1k

nockou

tmice

[83110

111]

Hydrogels

(hydroxyprop

yl)M

ethacrylam

ide

Cyclo

sporineA

anddo

xorubicin

ItinhibitstheP

-gpeffl

uxtransporterb

yincorporationof

drugssuchas

cyclo

sporine

AthatareP

-gpinhibitors

[112]

LipidNanocapsule

PEG-H

S(polyethyleneg

lycol-6


polymersandHPM

CEtop

osidea

ndtacrolim

us(1)Itinh

ibits

P-gp

efflux

byincorporationof

surfa

ctantb

ased

P-gp

inhibitors

[8389]

Triglycerid

esof

capricandcaprylic

acidsSolutol

Paclitaxel

(2)P

aclitaxelup

take

increasedin

MDR1

expressin

gcellsthe

half-lifeinbrain

prolon

gedfro

m21min

togt5h

Self-em

ulsifying

drug

deliverysyste

ms

Poly-m

ethacrylatep

olym

ers

Paclitaxeland

yacrolim

usItinhibitsP-gp

efflux

byincorporationof

surfa

ctantb

ased

P-gp

inhibitorsfor

exam

pleTw

een

[113114]

Medium

chaintriglycerid

ePE

G40

0po

lysorbate8

0andcrem

opho

rEL

Penfl

uridol(schizop

hreniatherapeutic

agent)

Itenhances

solubilizationof

drug

andthus

effectiv

ebrain

concentrations

Capm

ulMCM

-C8crem

opho

rELand

pluron

icL-121

Irinotecan


P-gp

mod

ulation

Nanosuspension

Pluron

icF6

8Risperidon

eP-gp

efflux

inhibitio

nby

employing

polymersthatinh

ibittheP

-gptransporter

such

aspluron

ic

[101]




10 Conclusions




References































































































































997888997888997888997888997888997888997888997888997888997888997888997888997888997888997888rarr



MRP1

MRP2

MRP3

MRP4

MRP6MRP5

P-gp BCRP

Apicalluminal

Basolateral

Blood

Brain


Tightjunction




times 100 (1)








CytosolP-gp

COOH

COOH

COOH

MRP1

TM TM

TM

NBD NBD

NBD

TMD0

L0

NH2

NH2

NH2

BCRP

(a)

Outer surface


Flippase model

(b)












2and

















Moderate [59 105]


Low [59 105]






















Natural polymers



[65]

Synthetic polymers



[65 66]

Pluronic P85


[66 68 69]

Thiomers


[71]








Nonthiolatedpolymer

Thiolatedpolymer



Mucousmembrane






























50values


100nm

5nm



















Endosomalrelease


P-gp P-gp

(A) (B)

(a)

(A) (B)

Core

Branchingpoints

Surfacegroups

Molecularcargo

123 z

zz

zzzzzz

zzz

zz z z z z z

zz

zz

z

G3 asymp 50nm

(b)






Table4

Drugdeliverysyste

mPo

lymer

Drug

Application

References

Nanocarrie

r(nanosph

eres)

Polyethylene

glycol

Polybu

tylcyano

acrylatealginate

polyethylene

glycolpolylactic

ndashco-

glycolicacidand

polylacticacid

Doxorub

icinclozapinem

etho

trexate

saqu

inavir

andzido

vudine

Drugmoleculeisd

elivered

tothec

ell

nucle

usandthus

avoids

recogn

ition

bythe


uxpu

mp

[83106ndash

108]

Lipo

somes

Phosph

olipidsa

ndcholesterol

Epiru

bicin

cisplatinm

etho

trexate

anddo

xorubicin

ItinhibitsP-gp

efflux

transporterb

yinteractionwith

phosph

olipidsthes

ystem

may

also

incorporateP

-gpinhibitors

[9596]

Polymer

nano

particles

Acrylic

polymerssuchas

poly-butyl-cyano

acrylate(PBC

A)

Loperamidea

nddo

xorubicin

Itbypasses

theP

-gpdu

eititsnano

size

[106]

Dendrim

ers

Manno

sylatedpo

ly(propyleneim

ine)

andpo

lyethylene

glycol-poly(am

idoamine)

Vinb

lastinedo

xorubicin

and

prop

rano

lol(intestinal)

ItinhibitsP-gp

efflux

bybypassingthep

ump

[97ndash99]

Nanogels

Catio

nica

ndno

n-ionicp

olym

ers

NVPNIPAM

Antise

nsep

hospho

rothioate

oligon

ucleotides

(SODN)a

nd5-flu

orou

racil

Itallowsfor

theincorpo

ratio

nof

P-gp

inhibitors

Polysorbatec

oatin

gof

nano

gelincreases


m018

to052

[83109]

Micelles

Pluron

icsL

61andF127

andP8

5Doxorub


riton

avir

andvinb

lastine

(1)Itinh

ibits

P-gp

efflux

andalso

involves

intracellulard

rugtransportm

odificatio

ntherebyavoiding

theP

-gpeffl

uxpu

mp

(2)D

rugperm

eabilityin

mon

olayered

BBB

mod

elby

P-gp

substrates

increasedfro

m16

-to

29-fo

ldN

ochange

indigoxin

concentrationin

mdr1k

nockou

tmice

[83110

111]

Hydrogels

(hydroxyprop

yl)M

ethacrylam

ide

Cyclo

sporineA

anddo

xorubicin

ItinhibitstheP

-gpeffl

uxtransporterb

yincorporationof

drugssuchas

cyclo

sporine

AthatareP

-gpinhibitors

[112]

LipidNanocapsule

PEG-H

S(polyethyleneg

lycol-6


polymersandHPM

CEtop

osidea

ndtacrolim

us(1)Itinh

ibits

P-gp

efflux

byincorporationof

surfa

ctantb

ased

P-gp

inhibitors

[8389]

Triglycerid

esof

capricandcaprylic

acidsSolutol

Paclitaxel

(2)P

aclitaxelup

take

increasedin

MDR1

expressin

gcellsthe

half-lifeinbrain

prolon

gedfro

m21min

togt5h

Self-em

ulsifying

drug

deliverysyste

ms

Poly-m

ethacrylatep

olym

ers

Paclitaxeland

yacrolim

usItinhibitsP-gp

efflux

byincorporationof

surfa

ctantb

ased

P-gp

inhibitorsfor

exam

pleTw

een

[113114]

Medium

chaintriglycerid

ePE

G40

0po

lysorbate8

0andcrem

opho

rEL

Penfl

uridol(schizop

hreniatherapeutic

agent)

Itenhances

solubilizationof

drug

andthus

effectiv

ebrain

concentrations

Capm

ulMCM

-C8crem

opho

rELand

pluron

icL-121

Irinotecan


P-gp

mod

ulation

Nanosuspension

Pluron

icF6

8Risperidon

eP-gp

efflux

inhibitio

nby

employing

polymersthatinh

ibittheP

-gptransporter

such

aspluron

ic

[101]




10 Conclusions




References





























































































































CytosolP-gp

COOH

COOH

COOH

MRP1

TM TM

TM

NBD NBD

NBD

TMD0

L0

NH2

NH2

NH2

BCRP

(a)

Outer surface


Flippase model

(b)












2and

















Moderate [59 105]


Low [59 105]






















Natural polymers



[65]

Synthetic polymers



[65 66]

Pluronic P85


[66 68 69]

Thiomers


[71]








Nonthiolatedpolymer

Thiolatedpolymer



Mucousmembrane






























50values


100nm

5nm



















Endosomalrelease


P-gp P-gp

(A) (B)

(a)

(A) (B)

Core

Branchingpoints

Surfacegroups

Molecularcargo

123 z

zz

zzzzzz

zzz

zz z z z z z

zz

zz

z

G3 asymp 50nm

(b)






Table4

Drugdeliverysyste

mPo

lymer

Drug

Application

References

Nanocarrie

r(nanosph

eres)

Polyethylene

glycol

Polybu

tylcyano

acrylatealginate

polyethylene

glycolpolylactic

ndashco-

glycolicacidand

polylacticacid

Doxorub

icinclozapinem

etho

trexate

saqu

inavir

andzido

vudine

Drugmoleculeisd

elivered

tothec

ell

nucle

usandthus

avoids

recogn

ition

bythe


uxpu

mp

[83106ndash

108]

Lipo

somes

Phosph

olipidsa

ndcholesterol

Epiru

bicin

cisplatinm

etho

trexate

anddo

xorubicin

ItinhibitsP-gp

efflux

transporterb

yinteractionwith

phosph

olipidsthes

ystem

may

also

incorporateP

-gpinhibitors

[9596]

Polymer

nano

particles

Acrylic

polymerssuchas

poly-butyl-cyano

acrylate(PBC

A)

Loperamidea

nddo

xorubicin

Itbypasses

theP

-gpdu

eititsnano

size

[106]

Dendrim

ers

Manno

sylatedpo

ly(propyleneim

ine)

andpo

lyethylene

glycol-poly(am

idoamine)

Vinb

lastinedo

xorubicin

and

prop

rano

lol(intestinal)

ItinhibitsP-gp

efflux

bybypassingthep

ump

[97ndash99]

Nanogels

Catio

nica

ndno

n-ionicp

olym

ers

NVPNIPAM

Antise

nsep

hospho

rothioate

oligon

ucleotides

(SODN)a

nd5-flu

orou

racil

Itallowsfor

theincorpo

ratio

nof

P-gp

inhibitors

Polysorbatec

oatin

gof

nano

gelincreases


m018

to052

[83109]

Micelles

Pluron

icsL

61andF127

andP8

5Doxorub


riton

avir

andvinb

lastine

(1)Itinh

ibits

P-gp

efflux

andalso

involves

intracellulard

rugtransportm

odificatio

ntherebyavoiding

theP

-gpeffl

uxpu

mp

(2)D

rugperm

eabilityin

mon

olayered

BBB

mod

elby

P-gp

substrates

increasedfro

m16

-to

29-fo

ldN

ochange

indigoxin

concentrationin

mdr1k

nockou

tmice

[83110

111]

Hydrogels

(hydroxyprop

yl)M

ethacrylam

ide

Cyclo

sporineA

anddo

xorubicin

ItinhibitstheP

-gpeffl

uxtransporterb

yincorporationof

drugssuchas

cyclo

sporine

AthatareP

-gpinhibitors

[112]

LipidNanocapsule

PEG-H

S(polyethyleneg

lycol-6


polymersandHPM

CEtop

osidea

ndtacrolim

us(1)Itinh

ibits

P-gp

efflux

byincorporationof

surfa

ctantb

ased

P-gp

inhibitors

[8389]

Triglycerid

esof

capricandcaprylic

acidsSolutol

Paclitaxel

(2)P

aclitaxelup

take

increasedin

MDR1

expressin

gcellsthe

half-lifeinbrain

prolon

gedfro

m21min

togt5h

Self-em

ulsifying

drug

deliverysyste

ms

Poly-m

ethacrylatep

olym

ers

Paclitaxeland

yacrolim

usItinhibitsP-gp

efflux

byincorporationof

surfa

ctantb

ased

P-gp

inhibitorsfor

exam

pleTw

een

[113114]

Medium

chaintriglycerid

ePE

G40

0po

lysorbate8

0andcrem

opho

rEL

Penfl

uridol(schizop

hreniatherapeutic

agent)

Itenhances

solubilizationof

drug

andthus

effectiv

ebrain

concentrations

Capm

ulMCM

-C8crem

opho

rELand

pluron

icL-121

Irinotecan


P-gp

mod

ulation

Nanosuspension

Pluron

icF6

8Risperidon

eP-gp

efflux

inhibitio

nby

employing

polymersthatinh

ibittheP

-gptransporter

such

aspluron

ic

[101]




10 Conclusions




References









































































































































Moderate [59 105]


Low [59 105]






















Natural polymers



[65]

Synthetic polymers



[65 66]

Pluronic P85


[66 68 69]

Thiomers


[71]








Nonthiolatedpolymer

Thiolatedpolymer



Mucousmembrane






























50values


100nm

5nm



















Endosomalrelease


P-gp P-gp

(A) (B)

(a)

(A) (B)

Core

Branchingpoints

Surfacegroups

Molecularcargo

123 z

zz

zzzzzz

zzz

zz z z z z z

zz

zz

z

G3 asymp 50nm

(b)






Table4

Drugdeliverysyste

mPo

lymer

Drug

Application

References

Nanocarrie

r(nanosph

eres)

Polyethylene

glycol

Polybu

tylcyano

acrylatealginate

polyethylene

glycolpolylactic

ndashco-

glycolicacidand

polylacticacid

Doxorub

icinclozapinem

etho

trexate

saqu

inavir

andzido

vudine

Drugmoleculeisd

elivered

tothec

ell

nucle

usandthus

avoids

recogn

ition

bythe


uxpu

mp

[83106ndash

108]

Lipo

somes

Phosph

olipidsa

ndcholesterol

Epiru

bicin

cisplatinm

etho

trexate

anddo

xorubicin

ItinhibitsP-gp

efflux

transporterb

yinteractionwith

phosph

olipidsthes

ystem

may

also

incorporateP

-gpinhibitors

[9596]

Polymer

nano

particles

Acrylic

polymerssuchas

poly-butyl-cyano

acrylate(PBC

A)

Loperamidea

nddo

xorubicin

Itbypasses

theP

-gpdu

eititsnano

size

[106]

Dendrim

ers

Manno

sylatedpo

ly(propyleneim

ine)

andpo

lyethylene

glycol-poly(am

idoamine)

Vinb

lastinedo

xorubicin

and

prop

rano

lol(intestinal)

ItinhibitsP-gp

efflux

bybypassingthep

ump

[97ndash99]

Nanogels

Catio

nica

ndno

n-ionicp

olym

ers

NVPNIPAM

Antise

nsep

hospho

rothioate

oligon

ucleotides

(SODN)a

nd5-flu

orou

racil

Itallowsfor

theincorpo

ratio

nof

P-gp

inhibitors

Polysorbatec

oatin

gof

nano

gelincreases


m018

to052

[83109]

Micelles

Pluron

icsL

61andF127

andP8

5Doxorub


riton

avir

andvinb

lastine

(1)Itinh

ibits

P-gp

efflux

andalso

involves

intracellulard

rugtransportm

odificatio

ntherebyavoiding

theP

-gpeffl

uxpu

mp

(2)D

rugperm

eabilityin

mon

olayered

BBB

mod

elby

P-gp

substrates

increasedfro

m16

-to

29-fo

ldN

ochange

indigoxin

concentrationin

mdr1k

nockou

tmice

[83110

111]

Hydrogels

(hydroxyprop

yl)M

ethacrylam

ide

Cyclo

sporineA

anddo

xorubicin

ItinhibitstheP

-gpeffl

uxtransporterb

yincorporationof

drugssuchas

cyclo

sporine

AthatareP

-gpinhibitors

[112]

LipidNanocapsule

PEG-H

S(polyethyleneg

lycol-6


polymersandHPM

CEtop

osidea

ndtacrolim

us(1)Itinh

ibits

P-gp

efflux

byincorporationof

surfa

ctantb

ased

P-gp

inhibitors

[8389]

Triglycerid

esof

capricandcaprylic

acidsSolutol

Paclitaxel

(2)P

aclitaxelup

take

increasedin

MDR1

expressin

gcellsthe

half-lifeinbrain

prolon

gedfro

m21min

togt5h

Self-em

ulsifying

drug

deliverysyste

ms

Poly-m

ethacrylatep

olym

ers

Paclitaxeland

yacrolim

usItinhibitsP-gp

efflux

byincorporationof

surfa

ctantb

ased

P-gp

inhibitorsfor

exam

pleTw

een

[113114]

Medium

chaintriglycerid

ePE

G40

0po

lysorbate8

0andcrem

opho

rEL

Penfl

uridol(schizop

hreniatherapeutic

agent)

Itenhances

solubilizationof

drug

andthus

effectiv

ebrain

concentrations

Capm

ulMCM

-C8crem

opho

rELand

pluron

icL-121

Irinotecan


P-gp

mod

ulation

Nanosuspension

Pluron

icF6

8Risperidon

eP-gp

efflux

inhibitio

nby

employing

polymersthatinh

ibittheP

-gptransporter

such

aspluron

ic

[101]




10 Conclusions




References











































































































































Natural polymers



[65]

Synthetic polymers



[65 66]

Pluronic P85


[66 68 69]

Thiomers


[71]








Nonthiolatedpolymer

Thiolatedpolymer



Mucousmembrane






























50values


100nm

5nm



















Endosomalrelease


P-gp P-gp

(A) (B)

(a)

(A) (B)

Core

Branchingpoints

Surfacegroups

Molecularcargo

123 z

zz

zzzzzz

zzz

zz z z z z z

zz

zz

z

G3 asymp 50nm

(b)






Table4

Drugdeliverysyste

mPo

lymer

Drug

Application

References

Nanocarrie

r(nanosph

eres)

Polyethylene

glycol

Polybu

tylcyano

acrylatealginate

polyethylene

glycolpolylactic

ndashco-

glycolicacidand

polylacticacid

Doxorub

icinclozapinem

etho

trexate

saqu

inavir

andzido

vudine

Drugmoleculeisd

elivered

tothec

ell

nucle

usandthus

avoids

recogn

ition

bythe


uxpu

mp

[83106ndash

108]

Lipo

somes

Phosph

olipidsa

ndcholesterol

Epiru

bicin

cisplatinm

etho

trexate

anddo

xorubicin

ItinhibitsP-gp

efflux

transporterb

yinteractionwith

phosph

olipidsthes

ystem

may

also

incorporateP

-gpinhibitors

[9596]

Polymer

nano

particles

Acrylic

polymerssuchas

poly-butyl-cyano

acrylate(PBC

A)

Loperamidea

nddo

xorubicin

Itbypasses

theP

-gpdu

eititsnano

size

[106]

Dendrim

ers

Manno

sylatedpo

ly(propyleneim

ine)

andpo

lyethylene

glycol-poly(am

idoamine)

Vinb

lastinedo

xorubicin

and

prop

rano

lol(intestinal)

ItinhibitsP-gp

efflux

bybypassingthep

ump

[97ndash99]

Nanogels

Catio

nica

ndno

n-ionicp

olym

ers

NVPNIPAM

Antise

nsep

hospho

rothioate

oligon

ucleotides

(SODN)a

nd5-flu

orou

racil

Itallowsfor

theincorpo

ratio

nof

P-gp

inhibitors

Polysorbatec

oatin

gof

nano

gelincreases


m018

to052

[83109]

Micelles

Pluron

icsL

61andF127

andP8

5Doxorub


riton

avir

andvinb

lastine

(1)Itinh

ibits

P-gp

efflux

andalso

involves

intracellulard

rugtransportm

odificatio

ntherebyavoiding

theP

-gpeffl

uxpu

mp

(2)D

rugperm

eabilityin

mon

olayered

BBB

mod

elby

P-gp

substrates

increasedfro

m16

-to

29-fo

ldN

ochange

indigoxin

concentrationin

mdr1k

nockou

tmice

[83110

111]

Hydrogels

(hydroxyprop

yl)M

ethacrylam

ide

Cyclo

sporineA

anddo

xorubicin

ItinhibitstheP

-gpeffl

uxtransporterb

yincorporationof

drugssuchas

cyclo

sporine

AthatareP

-gpinhibitors

[112]

LipidNanocapsule

PEG-H

S(polyethyleneg

lycol-6


polymersandHPM

CEtop

osidea

ndtacrolim

us(1)Itinh

ibits

P-gp

efflux

byincorporationof

surfa

ctantb

ased

P-gp

inhibitors

[8389]

Triglycerid

esof

capricandcaprylic

acidsSolutol

Paclitaxel

(2)P

aclitaxelup

take

increasedin

MDR1

expressin

gcellsthe

half-lifeinbrain

prolon

gedfro

m21min

togt5h

Self-em

ulsifying

drug

deliverysyste

ms

Poly-m

ethacrylatep

olym

ers

Paclitaxeland

yacrolim

usItinhibitsP-gp

efflux

byincorporationof

surfa

ctantb

ased

P-gp

inhibitorsfor

exam

pleTw

een

[113114]

Medium

chaintriglycerid

ePE

G40

0po

lysorbate8

0andcrem

opho

rEL

Penfl

uridol(schizop

hreniatherapeutic

agent)

Itenhances

solubilizationof

drug

andthus

effectiv

ebrain

concentrations

Capm

ulMCM

-C8crem

opho

rELand

pluron

icL-121

Irinotecan


P-gp

mod

ulation

Nanosuspension

Pluron

icF6

8Risperidon

eP-gp

efflux

inhibitio

nby

employing

polymersthatinh

ibittheP

-gptransporter

such

aspluron

ic

[101]




10 Conclusions




References





























































































































Nonthiolatedpolymer

Thiolatedpolymer



Mucousmembrane






























50values


100nm

5nm



















Endosomalrelease


P-gp P-gp

(A) (B)

(a)

(A) (B)

Core

Branchingpoints

Surfacegroups

Molecularcargo

123 z

zz

zzzzzz

zzz

zz z z z z z

zz

zz

z

G3 asymp 50nm

(b)






Table4

Drugdeliverysyste

mPo

lymer

Drug

Application

References

Nanocarrie

r(nanosph

eres)

Polyethylene

glycol

Polybu

tylcyano

acrylatealginate

polyethylene

glycolpolylactic

ndashco-

glycolicacidand

polylacticacid

Doxorub

icinclozapinem

etho

trexate

saqu

inavir

andzido

vudine

Drugmoleculeisd

elivered

tothec

ell

nucle

usandthus

avoids

recogn

ition

bythe


uxpu

mp

[83106ndash

108]

Lipo

somes

Phosph

olipidsa

ndcholesterol

Epiru

bicin

cisplatinm

etho

trexate

anddo

xorubicin

ItinhibitsP-gp

efflux

transporterb

yinteractionwith

phosph

olipidsthes

ystem

may

also

incorporateP

-gpinhibitors

[9596]

Polymer

nano

particles

Acrylic

polymerssuchas

poly-butyl-cyano

acrylate(PBC

A)

Loperamidea

nddo

xorubicin

Itbypasses

theP

-gpdu

eititsnano

size

[106]

Dendrim

ers

Manno

sylatedpo

ly(propyleneim

ine)

andpo

lyethylene

glycol-poly(am

idoamine)

Vinb

lastinedo

xorubicin

and

prop

rano

lol(intestinal)

ItinhibitsP-gp

efflux

bybypassingthep

ump

[97ndash99]

Nanogels

Catio

nica

ndno

n-ionicp

olym

ers

NVPNIPAM

Antise

nsep

hospho

rothioate

oligon

ucleotides

(SODN)a

nd5-flu

orou

racil

Itallowsfor

theincorpo

ratio

nof

P-gp

inhibitors

Polysorbatec

oatin

gof

nano

gelincreases


m018

to052

[83109]

Micelles

Pluron

icsL

61andF127

andP8

5Doxorub


riton

avir

andvinb

lastine

(1)Itinh

ibits

P-gp

efflux

andalso

involves

intracellulard

rugtransportm

odificatio

ntherebyavoiding

theP

-gpeffl

uxpu

mp

(2)D

rugperm

eabilityin

mon

olayered

BBB

mod

elby

P-gp

substrates

increasedfro

m16

-to

29-fo

ldN

ochange

indigoxin

concentrationin

mdr1k

nockou

tmice

[83110

111]

Hydrogels

(hydroxyprop

yl)M

ethacrylam

ide

Cyclo

sporineA

anddo

xorubicin

ItinhibitstheP

-gpeffl

uxtransporterb

yincorporationof

drugssuchas

cyclo

sporine

AthatareP

-gpinhibitors

[112]

LipidNanocapsule

PEG-H

S(polyethyleneg

lycol-6


polymersandHPM

CEtop

osidea

ndtacrolim

us(1)Itinh

ibits

P-gp

efflux

byincorporationof

surfa

ctantb

ased

P-gp

inhibitors

[8389]

Triglycerid

esof

capricandcaprylic

acidsSolutol

Paclitaxel

(2)P

aclitaxelup

take

increasedin

MDR1

expressin

gcellsthe

half-lifeinbrain

prolon

gedfro

m21min

togt5h

Self-em

ulsifying

drug

deliverysyste

ms

Poly-m

ethacrylatep

olym

ers

Paclitaxeland

yacrolim

usItinhibitsP-gp

efflux

byincorporationof

surfa

ctantb

ased

P-gp

inhibitorsfor

exam

pleTw

een

[113114]

Medium

chaintriglycerid

ePE

G40

0po

lysorbate8

0andcrem

opho

rEL

Penfl

uridol(schizop

hreniatherapeutic

agent)

Itenhances

solubilizationof

drug

andthus

effectiv

ebrain

concentrations

Capm

ulMCM

-C8crem

opho

rELand

pluron

icL-121

Irinotecan


P-gp

mod

ulation

Nanosuspension

Pluron

icF6

8Risperidon

eP-gp

efflux

inhibitio

nby

employing

polymersthatinh

ibittheP

-gptransporter

such

aspluron

ic

[101]




10 Conclusions




References













































































































































50values


100nm

5nm



















Endosomalrelease


P-gp P-gp

(A) (B)

(a)

(A) (B)

Core

Branchingpoints

Surfacegroups

Molecularcargo

123 z

zz

zzzzzz

zzz

zz z z z z z

zz

zz

z

G3 asymp 50nm

(b)






Table4

Drugdeliverysyste

mPo

lymer

Drug

Application

References

Nanocarrie

r(nanosph

eres)

Polyethylene

glycol

Polybu

tylcyano

acrylatealginate

polyethylene

glycolpolylactic

ndashco-

glycolicacidand

polylacticacid

Doxorub

icinclozapinem

etho

trexate

saqu

inavir

andzido

vudine

Drugmoleculeisd

elivered

tothec

ell

nucle

usandthus

avoids

recogn

ition

bythe


uxpu

mp

[83106ndash

108]

Lipo

somes

Phosph

olipidsa

ndcholesterol

Epiru

bicin

cisplatinm

etho

trexate

anddo

xorubicin

ItinhibitsP-gp

efflux

transporterb

yinteractionwith

phosph

olipidsthes

ystem

may

also

incorporateP

-gpinhibitors

[9596]

Polymer

nano

particles

Acrylic

polymerssuchas

poly-butyl-cyano

acrylate(PBC

A)

Loperamidea

nddo

xorubicin

Itbypasses

theP

-gpdu

eititsnano

size

[106]

Dendrim

ers

Manno

sylatedpo

ly(propyleneim

ine)

andpo

lyethylene

glycol-poly(am

idoamine)

Vinb

lastinedo

xorubicin

and

prop

rano

lol(intestinal)

ItinhibitsP-gp

efflux

bybypassingthep

ump

[97ndash99]

Nanogels

Catio

nica

ndno

n-ionicp

olym

ers

NVPNIPAM

Antise

nsep

hospho

rothioate

oligon

ucleotides

(SODN)a

nd5-flu

orou

racil

Itallowsfor

theincorpo

ratio

nof

P-gp

inhibitors

Polysorbatec

oatin

gof

nano

gelincreases


m018

to052

[83109]

Micelles

Pluron

icsL

61andF127

andP8

5Doxorub


riton

avir

andvinb

lastine

(1)Itinh

ibits

P-gp

efflux

andalso

involves

intracellulard

rugtransportm

odificatio

ntherebyavoiding

theP

-gpeffl

uxpu

mp

(2)D

rugperm

eabilityin

mon

olayered

BBB

mod

elby

P-gp

substrates

increasedfro

m16

-to

29-fo

ldN

ochange

indigoxin

concentrationin

mdr1k

nockou

tmice

[83110

111]

Hydrogels

(hydroxyprop

yl)M

ethacrylam

ide

Cyclo

sporineA

anddo

xorubicin

ItinhibitstheP

-gpeffl

uxtransporterb

yincorporationof

drugssuchas

cyclo

sporine

AthatareP

-gpinhibitors

[112]

LipidNanocapsule

PEG-H

S(polyethyleneg

lycol-6


polymersandHPM

CEtop

osidea

ndtacrolim

us(1)Itinh

ibits

P-gp

efflux

byincorporationof

surfa

ctantb

ased

P-gp

inhibitors

[8389]

Triglycerid

esof

capricandcaprylic

acidsSolutol

Paclitaxel

(2)P

aclitaxelup

take

increasedin

MDR1

expressin

gcellsthe

half-lifeinbrain

prolon

gedfro

m21min

togt5h

Self-em

ulsifying

drug

deliverysyste

ms

Poly-m

ethacrylatep

olym

ers

Paclitaxeland

yacrolim

usItinhibitsP-gp

efflux

byincorporationof

surfa

ctantb

ased

P-gp

inhibitorsfor

exam

pleTw

een

[113114]

Medium

chaintriglycerid

ePE

G40

0po

lysorbate8

0andcrem

opho

rEL

Penfl

uridol(schizop

hreniatherapeutic

agent)

Itenhances

solubilizationof

drug

andthus

effectiv

ebrain

concentrations

Capm

ulMCM

-C8crem

opho

rELand

pluron

icL-121

Irinotecan


P-gp

mod

ulation

Nanosuspension

Pluron

icF6

8Risperidon

eP-gp

efflux

inhibitio

nby

employing

polymersthatinh

ibittheP

-gptransporter

such

aspluron

ic

[101]




10 Conclusions




References







































































































































Endosomalrelease


P-gp P-gp

(A) (B)

(a)

(A) (B)

Core

Branchingpoints

Surfacegroups

Molecularcargo

123 z

zz

zzzzzz

zzz

zz z z z z z

zz

zz

z

G3 asymp 50nm

(b)






Table4

Drugdeliverysyste

mPo

lymer

Drug

Application

References

Nanocarrie

r(nanosph

eres)

Polyethylene

glycol

Polybu

tylcyano

acrylatealginate

polyethylene

glycolpolylactic

ndashco-

glycolicacidand

polylacticacid

Doxorub

icinclozapinem

etho

trexate

saqu

inavir

andzido

vudine

Drugmoleculeisd

elivered

tothec

ell

nucle

usandthus

avoids

recogn

ition

bythe


uxpu

mp

[83106ndash

108]

Lipo

somes

Phosph

olipidsa

ndcholesterol

Epiru

bicin

cisplatinm

etho

trexate

anddo

xorubicin

ItinhibitsP-gp

efflux

transporterb

yinteractionwith

phosph

olipidsthes

ystem

may

also

incorporateP

-gpinhibitors

[9596]

Polymer

nano

particles

Acrylic

polymerssuchas

poly-butyl-cyano

acrylate(PBC

A)

Loperamidea

nddo

xorubicin

Itbypasses

theP

-gpdu

eititsnano

size

[106]

Dendrim

ers

Manno

sylatedpo

ly(propyleneim

ine)

andpo

lyethylene

glycol-poly(am

idoamine)

Vinb

lastinedo

xorubicin

and

prop

rano

lol(intestinal)

ItinhibitsP-gp

efflux

bybypassingthep

ump

[97ndash99]

Nanogels

Catio

nica

ndno

n-ionicp

olym

ers

NVPNIPAM

Antise

nsep

hospho

rothioate

oligon

ucleotides

(SODN)a

nd5-flu

orou

racil

Itallowsfor

theincorpo

ratio

nof

P-gp

inhibitors

Polysorbatec

oatin

gof

nano

gelincreases


m018

to052

[83109]

Micelles

Pluron

icsL

61andF127

andP8

5Doxorub


riton

avir

andvinb

lastine

(1)Itinh

ibits

P-gp

efflux

andalso

involves

intracellulard

rugtransportm

odificatio

ntherebyavoiding

theP

-gpeffl

uxpu

mp

(2)D

rugperm

eabilityin

mon

olayered

BBB

mod

elby

P-gp

substrates

increasedfro

m16

-to

29-fo

ldN

ochange

indigoxin

concentrationin

mdr1k

nockou

tmice

[83110

111]

Hydrogels

(hydroxyprop

yl)M

ethacrylam

ide

Cyclo

sporineA

anddo

xorubicin

ItinhibitstheP

-gpeffl

uxtransporterb

yincorporationof

drugssuchas

cyclo

sporine

AthatareP

-gpinhibitors

[112]

LipidNanocapsule

PEG-H

S(polyethyleneg

lycol-6


polymersandHPM

CEtop

osidea

ndtacrolim

us(1)Itinh

ibits

P-gp

efflux

byincorporationof

surfa

ctantb

ased

P-gp

inhibitors

[8389]

Triglycerid

esof

capricandcaprylic

acidsSolutol

Paclitaxel

(2)P

aclitaxelup

take

increasedin

MDR1

expressin

gcellsthe

half-lifeinbrain

prolon

gedfro

m21min

togt5h

Self-em

ulsifying

drug

deliverysyste

ms

Poly-m

ethacrylatep

olym

ers

Paclitaxeland

yacrolim

usItinhibitsP-gp

efflux

byincorporationof

surfa

ctantb

ased

P-gp

inhibitorsfor

exam

pleTw

een

[113114]

Medium

chaintriglycerid

ePE

G40

0po

lysorbate8

0andcrem

opho

rEL

Penfl

uridol(schizop

hreniatherapeutic

agent)

Itenhances

solubilizationof

drug

andthus

effectiv

ebrain

concentrations

Capm

ulMCM

-C8crem

opho

rELand

pluron

icL-121

Irinotecan


P-gp

mod

ulation

Nanosuspension

Pluron

icF6

8Risperidon

eP-gp

efflux

inhibitio

nby

employing

polymersthatinh

ibittheP

-gptransporter

such

aspluron

ic

[101]




10 Conclusions




References





























































































































Table4

Drugdeliverysyste

mPo

lymer

Drug

Application

References

Nanocarrie

r(nanosph

eres)

Polyethylene

glycol

Polybu

tylcyano

acrylatealginate

polyethylene

glycolpolylactic

ndashco-

glycolicacidand

polylacticacid

Doxorub

icinclozapinem

etho

trexate

saqu

inavir

andzido

vudine

Drugmoleculeisd

elivered

tothec

ell

nucle

usandthus

avoids

recogn

ition

bythe


uxpu

mp

[83106ndash

108]

Lipo

somes

Phosph

olipidsa

ndcholesterol

Epiru

bicin

cisplatinm

etho

trexate

anddo

xorubicin

ItinhibitsP-gp

efflux

transporterb

yinteractionwith

phosph

olipidsthes

ystem

may

also

incorporateP

-gpinhibitors

[9596]

Polymer

nano

particles

Acrylic

polymerssuchas

poly-butyl-cyano

acrylate(PBC

A)

Loperamidea

nddo

xorubicin

Itbypasses

theP

-gpdu

eititsnano

size

[106]

Dendrim

ers

Manno

sylatedpo

ly(propyleneim

ine)

andpo

lyethylene

glycol-poly(am

idoamine)

Vinb

lastinedo

xorubicin

and

prop

rano

lol(intestinal)

ItinhibitsP-gp

efflux

bybypassingthep

ump

[97ndash99]

Nanogels

Catio

nica

ndno

n-ionicp

olym

ers

NVPNIPAM

Antise

nsep

hospho

rothioate

oligon

ucleotides

(SODN)a

nd5-flu

orou

racil

Itallowsfor

theincorpo

ratio

nof

P-gp

inhibitors

Polysorbatec

oatin

gof

nano

gelincreases


m018

to052

[83109]

Micelles

Pluron

icsL

61andF127

andP8

5Doxorub


riton

avir

andvinb

lastine

(1)Itinh

ibits

P-gp

efflux

andalso

involves

intracellulard

rugtransportm

odificatio

ntherebyavoiding

theP

-gpeffl

uxpu

mp

(2)D

rugperm

eabilityin

mon

olayered

BBB

mod

elby

P-gp

substrates

increasedfro

m16

-to

29-fo

ldN

ochange

indigoxin

concentrationin

mdr1k

nockou

tmice

[83110

111]

Hydrogels

(hydroxyprop

yl)M

ethacrylam

ide

Cyclo

sporineA

anddo

xorubicin

ItinhibitstheP

-gpeffl

uxtransporterb

yincorporationof

drugssuchas

cyclo

sporine

AthatareP

-gpinhibitors

[112]

LipidNanocapsule

PEG-H

S(polyethyleneg

lycol-6


polymersandHPM

CEtop

osidea

ndtacrolim

us(1)Itinh

ibits

P-gp

efflux

byincorporationof

surfa

ctantb

ased

P-gp

inhibitors

[8389]

Triglycerid

esof

capricandcaprylic

acidsSolutol

Paclitaxel

(2)P

aclitaxelup

take

increasedin

MDR1

expressin

gcellsthe

half-lifeinbrain

prolon

gedfro

m21min

togt5h

Self-em

ulsifying

drug

deliverysyste

ms

Poly-m

ethacrylatep

olym

ers

Paclitaxeland

yacrolim

usItinhibitsP-gp

efflux

byincorporationof

surfa

ctantb

ased

P-gp

inhibitorsfor

exam

pleTw

een

[113114]

Medium

chaintriglycerid

ePE

G40

0po

lysorbate8

0andcrem

opho

rEL

Penfl

uridol(schizop

hreniatherapeutic

agent)

Itenhances

solubilizationof

drug

andthus

effectiv

ebrain

concentrations

Capm

ulMCM

-C8crem

opho

rELand

pluron

icL-121

Irinotecan


P-gp

mod

ulation

Nanosuspension

Pluron

icF6

8Risperidon

eP-gp

efflux

inhibitio

nby

employing

polymersthatinh

ibittheP

-gptransporter

such

aspluron

ic

[101]




10 Conclusions




References































































































































10 Conclusions




References




























































































































bypassing p-glycoprotein drug efflux mechanisms: possible ... · extended phenotype: general...

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