GENETIC POLYMORPHISM

IN DRUG

TRANSPORTAND

DRUG TARGETSPREPARED BY :

RUMANA HAMEEDPHARM D

170310820021

DRUG TARGETS:Targeted drug delivery is a method of delivering medication to a patient in a manner that increases the concentration of the medication in some parts of the body relative to others.

Objective:• Provide therapeutic concentration of

drugs at the site of action• Reduce systemic toxicity• Increase patient compliance• This improves efficacy of the drug

while reducing side effects.

Classification of Drug Targeting

Drug targeting has been classified into three types:

First Order

It refers to restricted distribution of the drug-carrier system to the capillary bed of a predetermined target site, organ or tissue. Compartmental targeting in lymphatics*, peritoneal cavity, cerebral ventricles, lungs, joints, eyes, etc.

Second Order

The selective delivery of drugs to a specific cell type such as tumor cells and not to the normal cells is referred as second order drug targeting. The selective drug delivery to the Kupffer cells in the liver** exemplifies this approach.

Third Order

The third order targeting is defined as drug delivery specifically to the intracellular site of target cells. The receptor based ligand-mediated entry of drug complex into a cell by endocytosis, lysosomal degradation of carrier followed by release of drug intra-cellularly or gene delivery to nucleolus is an example for this approach.

Direct local application

Tumor microenvironment

Leaky Vasculature

Antibody targeted

Carbohydrate targeted

Receptor targeted

Drug TargetingPrincipal schemes of drug targeting currently investigated in various

experimental and clinical settings include:

• Direct application of the drug into the affected zone (organ, tissue)

• Passive accumulation of the drug through leaky vasculature (tumors, infarcts, inflammation)

• ‘physical’ targeting based on abnormal pH and / or temperature in the target zone, such as tumor or inflammation (pH- and temperature-sensitive drug carriers)

• Magnetic targeting of drugs attached to paramagnetic carriers under the action of external magnetic field

• Use of vector molecules possessing high specific affinity toward the affected zone

The parameters determining the efficacy of drug targeting:

• Size of the target• Blood flow through the target• Number of binding sites for the

targeted drug/ drug carrier within the target

• Number and affinity of targeting moieties

Passive targeting

approachesPathophysiological factors – Inflammation, Infection, EPR effect

Physicochemical factors – Size, Molecular weight

Anatomical opportunities – Catheterization, Direct injection

Chemical approaches – Prodrugs, Chemical delivery systems

Active targeting approachesCarrier specificity can be enhanced, through surface

functionalization with site-directed ligands which bind or interact with specific tissues

Biochemical targets – Organs, Cellular, Organelles,

Intracellular

Physical/External Stimuli – Ultrasound,

Magnetic field

Main Approaches to Targeting

Retrometabolic Systems:

Individual drug molecules chemically modified to target particularly to the disease site.

Carrier – Based Systems:

Drug is first packaged non-covalently into a synthetic Carrier that is then targeted to the disease site.

Drug Targeting: Prodrugs

Compounds that undergo biotransformation prior to exhibiting pharmacological effect

Prodrug Continuing:Overcoming Barriers

Chemically linking pro-moiety to form prodrug

Biotransformation

Release of parent drug

Barrier is circumvented

Examples:6-Monoacetylmorphine (6-MAM) is a heroin metabolite which converts into active morphine in vivo.Prednisone, a synthetic cortico-steroid drug, is bioactivated by the liver into the active drug prednisolone.

Drug Targeting: Magnetic Drug Targeting

•Using magnetic nanoparticles (ferrofluids)• Enhancing efficacy• Minimum side effects

• Ferromagnetic element (e.g. an implant) is placed in a magnetic field, it becomes magnetically energized

The Biophysical Targeting Technique

Solid tumor

Apply magnetic field to concentrate particles

Modulate field to release drug from particles

Inject NMPs IV,NMP will circulate through the blood stream

Other options:1 - Direct injection into tumor site2 - Coating NMP with antibodies to target

Magnetic Drug Targeting Continuing: Guided Drug Delivery

Ability to add localized heating combined with drug delivery

Magnetic Drug Targeting Continuing: Advantages

Magnetic drug targeting is used to treat malignant tumors loco-regionally without systemic toxicity.

Magnetic particles used as “carrier system” for a variety of anticancer agents, e.g. radionuclides, cancer – specific antibodies, and genes

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Drug Targeting: LIPOSOMES

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These are vesicular concentric structures, range in size from a nanometer to several micrometers, containing a phospholipids bilayer and are biocompatible, biodegradable and non immunogenic.

Liposomes have generated a great interest because of their versatility and have played a significant role in formulation of potent drugs to improve therapeutics. Enhanced safety and efficacy have been achieved for a wide range of drug classes, including antitumor agents, antiviral, antimicrobials, vaccines, gene therapeutics etc.

Two-Steps Targeting

Specifically binding to tumor cell

Bind chromosomal DNA in

target tumor cell

Drug Targeting: TransdermalApproach

Transdermal drug delivery system is topically administered medicaments in the form of patches that deliver drugs for systemic effects at a predetermined and controlled rate.

A transdermal drug delivery device, which may be of an active or a passive design, is a device which provides an alternative route for administering medication. These devices allow for pharmaceuticals to be delivered across the skin barrier.

Transdermal Approach Continuing:

In theory, transdermal patches work very simply. A drug is applied in a relatively high dosage to the inside of a patch, which is worn on the skin for an extended period of time. Through a diffusion process, the drug enters the bloodstream directly through the skin.

Since there is high concentration on the patch and low concentration in the blood, the drug will keep diffusing into the blood for a long period of time, maintaining the constant concentration of drug in the blood flow.

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Drug Targeting: Brain targeted drug delivery system

The brain is a delicate organ, and evolution built very efficient ways to protect it. The delivery of drugs to central nervous system (CNS) is a challenge in the treatment of neurological disorders.

Drugs may be administered directly into the CNS or administered systematically (e.g., by intravenous injection) for targeted action in the CNS. The major challenge to CNS drug delivery is the blood-brain barrier (BBB), which limits the access of drugs to the brain substance.

Fig: Central Nervous System-selective Estrogens: A Safe Estrogen Therapy

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Brain targeted drug delivery system Continuing:

Advances in understanding of the cell biology of the BBB have opened new avenues and possibilities for improved drug delivery to the CNS.

Various strategies that have been used for manipulating the blood-brain barrier for drug delivery to the brain include osmotic and chemical opening of the blood-brain barrier as well as the use of transport/carrier systems.

Other strategies for drug delivery to the brain involve bypassing the BBB. Various pharmacological agents have been used to open the BBB and direct invasive methods can introduce therapeutic agents into the brain substance.

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ConclusionResearch related to the development of targeted drug delivery system is now a day is highly preferred and facilitating field of pharmaceutical world. It has crossed the infancy period and now touching height of growths from the pharmacy point of view.

Targeted delivery of drugs, as the name suggests, is to assist the drug molecule to reach preferably to the desired site. The inherent advantage of this technique has been the reduction in dose & side effect of the drug.

Overall it may be concluded with the vast database of different studies, the science of site specific or targeted delivery of these drugs has become wiser. Manifestation of these strategies in clinical now seems possible in near future.

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Introduction Transporters are those proteins that carry either endogenous compounds or xenobiotics across biological membranes.

They can be classified into either efflux or uptake proteins, depending on the direction of transport.

The extent of expression of genes coding for transport proteins can have a profound effect on the bioavailability and pharmacokinetics of various drugs.

Additionally, genetic variation such as single-nucleotide polymorphisms (SNPs) of the transport proteins can cause differences in the uptake or efflux of drugs.

In terms of cancer chemotherapy, tumor cells expressing these proteins can have either enhanced sensitivity or resistance to various anticancer drugs.

Transporters that serve as efflux pumps on a cell membrane can remove drugs from the cell before they can act.

Transport proteins that are responsible for the vital influx of ions and nutrients such as glucose can promote growth of tumor cells if overexpressed, or lead to increased susceptibility for a drug if the transporter carries that drug into the cell.

Importance of Drug Transporter

Role in overall disposition of drugs to the target organs

Significant determinant of drug-drug interaction

Variability in drug response

Types of drug transporter

Two types of transporter :

ATP binding Cassette (ABC) – Found in ABCB, ABCD and ABCG family. Associated with multidrug resistance (MDR) of tumor cells causing treatment failure in cancer.

Solute Carrier (SLC) – Transport varieties of solute include both charged or uncharged

Comparison ATP Binding

CassetteSolute Carrier

Efflux transporter Influx / bidirectional transporter

Utilize energy from ATP

Electrochemical gradient / facilitated diffusion

Primary active Secondary activeSubfamilies : ABCA, ABCB, ABCD, ABCE, ABCDF, ABCG

Subfamilies ; SLC15, SLC22, SLCO

P-glycoprotein

• ATP binding cassette sub family B member-1 (ABCB 1)

• Multidrug resistance protein 1 (MDR1)

• Transport various molecules, including xenobiotic, across cell membrane

• Extensively distributed and expressed throughout the body

Function of P-glycoproteinSite of

transportationFunction

Liver – Bile Elimination

Kidney - Urine Excretion

Placenta – Maternal blood Protect fetal from drug exposure

Intestine – Intestinal lumen

Reduce drug absorption into the blood

Brain – Blood Monitor drug access to the brain

Mechanism of P-glycoprotein

① Substrate bind to P-gp form the inner leaflet of the membrane

② ATP binds at the inner side of the protein

③ ATP is hydrolyzed to produce ADP and energy

④ Substrate is excreted outside the cell

Clinical Importance

P-gp is a multidrug resistant protein (MDR)

Role of P-gp is significant in tumor cells. Expression of P-gp in tumor cells reduces the accessibility of cytotoxic drugs by eliminating them in various pathways. Hence, P-gp may act as a major barrier to effective drug treatments.

Over expression of P-gp in limit the treatment for cancer, AIDS, Alzheimer’s and epilepsy.

ReferencesDean M, Hamon Y, Chimini G (July 2001). "The human ATP-binding cassette (ABC) transporter superfamily”

Hediger MA, Romero MF, Peng JB, Rolfs A, Takanaga H, Bruford EA (2004). "The ABCs of solute carriers: physiological, pathological and therapeutic implications of human membrane transport proteins: Introduction”

Dean, Michael (2002-11-01). "The Human ATP-Binding Cassette (ABC) Transporter Superfamily”

Peter N Bennett, Morris J Brown, Pankaj Sharma, 11th Edition (2012). “Clinical Pharmacology”

Department of Drug Metabolism, Merck Research Laboratories (Nov 2003). “Clinical relevance of P-glycoprotein in drug therapy”

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