PHARMACOKINETICSPHARMACOKINETICS

DefinitionDefinition: quantitative study of : quantitative study of drug absorption, distribution, drug absorption, distribution,

metabolism, and excretion metabolism, and excretion ((ADMEADME), and their mathematical ), and their mathematical

relationship.relationship.

PHARMACOKINETICSPHARMACOKINETICS

absorptionabsorption distributiondistribution excretionexcretionmetabolismmetabolism

DispositionDisposition: term used to describe : term used to describe the simultaneous effect of the the simultaneous effect of the distribution and elimination distribution and elimination (processes subsequent to (processes subsequent to

absorption).absorption).

AbsorptionAbsorption AbsorptionAbsorption: passage of drug through : passage of drug through

body barriers.body barriers. Transmembrane movement of drugs:Transmembrane movement of drugs: Passive transfer:Passive transfer:

– Simple diffusionSimple diffusion– FiltrationFiltration

N.B.: Diffusion is most important N.B.: Diffusion is most important means. It is affected by: size of means. It is affected by: size of molecule, conc. Gradient, surface molecule, conc. Gradient, surface area, permeability coefficient. (FICK'S area, permeability coefficient. (FICK'S Law).Law).

N.B.: Permeability coeffiecient varies according to the concentration of

ionized and nonionized form of the drug on both sides of the membrane, determined by pka of the drug.

Henderson Hasselbalch equationpH=pka + log [nonprotonated species/

protonated species]

Specialized transport

– Active transport

1-1ry active transport 2- 2ndry active transport

(Cotransport,countertransport)

– Facilitated diffusion

– Pinocytosis and phagocytosis

Bioavailability: percentage of drug released from a formulation that becomes available for biological effect.

Factors affecting bioavailability:Factors affecting bioavailability:

a)Factors affecting absorption from a)Factors affecting absorption from GIT:GIT:

1-Drug1-Drug2-Formulation2-Formulation3-Patients3-Patients4-Food.4-Food. b) First pass effect: presystemic b) First pass effect: presystemic

elimination.It is the metabolism of elimination.It is the metabolism of some drugs in a single passage some drugs in a single passage through the liver, gut walls, or lungs through the liver, gut walls, or lungs before reaching the systemic before reaching the systemic circulation.circulation.

Hepatic: e.g.:propranolol, nitroglycerin,cortisone.Pulmonary: isoprenaline,nicotine.Intestinal: tyramine,morphine.

*Pulmonary Absorption*Absorption from subcutaneous

tissues*Methods for delaying absorption:

a.oral b.parenteral.

DistributionDistribution

Passage of drug between blood and Passage of drug between blood and tissues.tissues.

Compartment concept: Compartment concept: - one-compartment model- one-compartment model -Two- compartment model-Two- compartment model Mathematically, apparent volume of Mathematically, apparent volume of

distribution (Vd): apparent volume distribution (Vd): apparent volume that would accommodate all drug in that would accommodate all drug in the body if its conc. throughout the the body if its conc. throughout the body was the same as that in the body was the same as that in the plasma (not real).plasma (not real).

N.B.: small volume of N.B.: small volume of distribution is favored by low distribution is favored by low lipid solubility, high degree lipid solubility, high degree of plasma protein binding of plasma protein binding and low level of tissue and low level of tissue binding, & vice-versa.binding, & vice-versa.

Vd = amount of drug in the body / plasma Vd = amount of drug in the body / plasma concentration.concentration.

Importance:Importance:-extent of tissue up-take-extent of tissue up-take-calculation of loading dose-calculation of loading dose- dialysis- dialysis

Factors affecting distribution of drugs:Factors affecting distribution of drugs:1-Physicochemical properties1-Physicochemical properties2-Size of the tissue and its blood flow.2-Size of the tissue and its blood flow.3-Binding to plasma proteins: a- 3-Binding to plasma proteins: a- AlbuminAlbumin b-b-α-1-acid glycoproteinα-1-acid glycoprotein4-Binding to cell and tissue components4-Binding to cell and tissue components

Results of binding to plasma Results of binding to plasma proteins:proteins:

1-drugs with higher affinity can 1-drugs with higher affinity can displace those with lower.displace those with lower.

2-Reservoir2-Reservoir

3-Prolongs t 1/2.3-Prolongs t 1/2.

4-Determines Vd4-Determines Vd

5-may facilitate absorption5-may facilitate absorption

The bound portion is The bound portion is inactive,nondiffusible, & cannot inactive,nondiffusible, & cannot be metabolized or excreted.be metabolized or excreted.

– BBBBBB

– Placental barrierPlacental barrier

Biotransformation"metabolismBiotransformation"metabolism""

Def.: changes that occur to drug Def.: changes that occur to drug after absorption until excretion.after absorption until excretion.

Consequences:Consequences:

-abolishes activity-abolishes activity

-promotes activity-promotes activity

-changes active to another active -changes active to another active form.form.

Types of reaction:Types of reaction:-Non-synthetic (phase-I): oxidation, -Non-synthetic (phase-I): oxidation,

reduction, and hydrolysis.reduction, and hydrolysis.

-Synthetic (phase-II): adds a constituent -Synthetic (phase-II): adds a constituent to the drug to form highly polar to the drug to form highly polar rapidly eliminated rapidly eliminated conjugates"Conjugation". These conjugates"Conjugation". These include: glucoronic acid,N-include: glucoronic acid,N-acetylation,glycine and sulphuric acid acetylation,glycine and sulphuric acid conjugation.conjugation.

Factors affecting biotransformation: Factors affecting biotransformation: species,age,sex, pathological species,age,sex, pathological conditions,environmental factors.conditions,environmental factors.

Microsomal enzymes:Microsomal enzymes: SER of liver.SER of liver.1-MFO, that requires cytochrome P-450, 1-MFO, that requires cytochrome P-450,

NADPH,molecular oxygenNADPH,molecular oxygen2-metabolize lipid soluble to water soluble 2-metabolize lipid soluble to water soluble

drugsdrugs3-metabolize drugs as well s body as body 3-metabolize drugs as well s body as body

constituentsconstituents4-lack substrate specificity4-lack substrate specificity5-not well developed in newborn.5-not well developed in newborn.

Non-microsomal enzyme systems: e.g.-Non-microsomal enzyme systems: e.g.-peroxidases, oxidases,and dehydrogenases.peroxidases, oxidases,and dehydrogenases.

N.B.: Enzyme inductionN.B.: Enzyme induction Enzyme inhibition.Enzyme inhibition.

Drug ClearanceDrug Clearance A measure of the body's ability to A measure of the body's ability to

eliminate drugs. It's defined as the eliminate drugs. It's defined as the volume of a fluid from which all drug volume of a fluid from which all drug is removed per unit time.is removed per unit time.

CLEARNCE (CL)= Rate of elimination / CLEARNCE (CL)= Rate of elimination / Drug conc.Drug conc.

May involve: kidney, liver, lungs, and May involve: kidney, liver, lungs, and other organs.other organs.

Factors affecting clearance:Factors affecting clearance:– Blood flowBlood flow– binding to plasma proteinsbinding to plasma proteins– activity of the processes involving activity of the processes involving

blood removal(e.g.: hepatic blood removal(e.g.: hepatic enzymes…etc).enzymes…etc).

N.B.: hepatic clearance depends N.B.: hepatic clearance depends on: intrinsic activity of metabolic on: intrinsic activity of metabolic enzymes and transport enzymes and transport processes, free fraction of drug processes, free fraction of drug and total effective blood flow.and total effective blood flow.

Elimination half-life: the time Elimination half-life: the time required to reduce the plasma required to reduce the plasma concentration of drug to 1/2 the concentration of drug to 1/2 the initial conc.initial conc.

t (1/2)=0.693 Vd / CLt (1/2)=0.693 Vd / CL

Value of t (1/2):Value of t (1/2):

-time required to attain Css.-time required to attain Css.

-Determines dosage interval ( usually = -Determines dosage interval ( usually = t 1/2)t 1/2)

-Index of drug elimination-Index of drug elimination

Firstorder (non-saturable) Firstorder (non-saturable) kinetics:kinetics:

Clearance is directly proportional Clearance is directly proportional to the conc. o the drug in the to the conc. o the drug in the plasma, i.e.; the rate of elimination plasma, i.e.; the rate of elimination is exponentially related to the is exponentially related to the amount of drug available. This amount of drug available. This means that a constant fraction or means that a constant fraction or ratio of drug is eliminated per unit ratio of drug is eliminated per unit time.time.

Characteristics: Characteristics:

Constant t1/2.Constant t1/2. AUC, Css and amount of drug AUC, Css and amount of drug

excreted unchanged in urine; all excreted unchanged in urine; all are proportional to the dose.are proportional to the dose.

Composition of the drug Composition of the drug metabolites excreted is metabolites excreted is independent of the dose.independent of the dose.

Zero-order kinetics (non-linear):Zero-order kinetics (non-linear):Drug elimination occurs at a constant Drug elimination occurs at a constant

rate of the amount of drug to be rate of the amount of drug to be eliminated. This means that a eliminated. This means that a constant amount of drug being constant amount of drug being eliminated per unit time.eliminated per unit time.

Characteristics:Characteristics:1. Half-life increases with dose1. Half-life increases with dose2. AUC, Css and amount of drug 2. AUC, Css and amount of drug

excreted unchanged in urine; all not excreted unchanged in urine; all not proportional to the dose.proportional to the dose.

3. Composition of the drug metabolites 3. Composition of the drug metabolites excreted may varyexcreted may vary

with the dose.with the dose.

Saturable kinetics:Saturable kinetics:

The elimination does not follow The elimination does not follow first-order kinetics throughout the first-order kinetics throughout the dose range. Clearance will vary dose range. Clearance will vary depending on the achieved drug depending on the achieved drug concentration. Many ADME processes concentration. Many ADME processes occur via enzymes or carrier-occur via enzymes or carrier-mediated systems which for these mediated systems which for these drugs become saturated in the drugs become saturated in the therapeutic range and results in therapeutic range and results in saturable non-linear elimination saturable non-linear elimination kinetics. Modest changes in dose or kinetics. Modest changes in dose or bioavailaility of these drugs may bioavailaility of these drugs may produce unexpected toxicity.produce unexpected toxicity.