Basics of Pharmacokinetics Level Intermediate Version No 1

Basics of Pharmacokinetics Level : Intermediate Version No: 1 Version Date: December 2013 Prepared by: Balram Chowbay, Ph. D Principal Pharmacologist Clinical Pharmacology Lab National Cancer Center Narrated by: Natalia Sutiman

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Pharmacokinetics vs. Pharmacodynamics What the body does to the drug vs. What the drug does to the body

Pharmacokinetics (PK) • The study of the time course of drug action in the body Absorption Metabolism Elimination Pharmacokinetics (PK) Excretion Distribution

Pharmacokinetics: ADME

Pharmacokinetics (PK) Absorption Pharmacokinetics (PK)

Routes of Drug Administration Via alimentary canal Intravenous Oral Buccal Rectal Sublingual Other routes Intranasal Inhalation Transdermal Subcutaneous Intramuscular

Absorption • Absorption refers to the transfer of drug from site of administration to site of measurement

Disintegration, Deaggregation & Dissolution

Factors influencing absorption 1. Drug properties – Drug formulation and dosage form – Molecular size of a drug – Lipophilicity and polarity of drug compound 2. Properties of absorption site – – – Blood flow to absorption site p. H of the absorption site Area of absorption site Permeability of the membrane (e. g. BBB, gut wall) Presence of drug transporters

Factors influencing absorption 3. Other factors – – Food intake Presence of disease states and other abnormalities Co-administration with other drugs First-pass loss/ pro-drugs

Pharmacokinetics (PK) Absorption Pharmacokinetics (PK) Distribution

Distribution • Reversible transfer of a drug to and from the site of measurement (intravascular) and the peripheral tissues (extravascular) • Mathematically described as apparent volume of distribution (Vd) • Volume into which a drug appears to be dissolved to account for its plasma concentration • Vd = Doseiv / C

Volume of Distribution (Vd) • Vd does not refer to actual physiological volume – Vd of digoxin = 420 L – Vd of chloroquine = 13000 L • Large Vd indicates that the drug distributes extensively into body tissues and fluids while a small Vd indicates limited drug distribution, mostly only in plasma

Factors influencing distribution • Blood perfusion • Presence of influx and efflux transporters on membrane surface • Lipid solubility (lipid: water partition coefficient) • p. Ka of the drug and regional p. H • Plasma protein binding • Tissue protein binding • Disease states

Enterohepatic Recycling

Pharmacokinetics (PK) Absorption Metabolism Elimination Pharmacokinetics (PK) Excretion Distribution

Elimination • Refers to the irreversible loss of drug compound from the site of measurement • Includes both metabolism and excretion Metabolism Metabolites Drug in the body Excretion Unchanged drug in urine

Routes of Elimination • Organs involved in drug elimination: liver, kidney, lung, skin, walls of the gut • Terms to describe elimination – Clearance: Volume of fluid presented to the eliminating organ that is completely cleared of drug each minute. – Elimination half-life: time taken for the concentration of the drug to fall by one half.

Elimination • PK parameters to describe elimination – Clearance: Volume of fluid presented to the eliminating organ that is completely cleared of drug each minute. – Elimination half-life: time taken for the concentration of the drug to fall by one half. t 1/2 A t 1/2 B Different half-lives

Pharmacokinetics (PK) Absorption Metabolism Pharmacokinetics (PK) Distribution

Metabolism • Refers to the conversion of one chemical species to another • Aims to convert less polar (more lipid soluble) parent drugs to more polar entities – Most hydrophilic (polar) drugs are excreted unchanged e. g. streptomycin, neostigmine • Also includes the bio-activation of pro-drugs into their active metabolites • Organs involved: Liver, gastrointestinal tract, kidney, lungs

Phases of Drug Metabolism • Phase I reactions – Convert parent drug into more polar metabolite(s) by adding or unmasking functional groups (-OH, -NH 2, COOH, etc) – Usually precede phase II reactions • Phase II reactions – Conjugate parent drug or metabolite(s) with endogenous substrate (glucuronic acid, sulfate, acetate, etc) to further increase aqueous solubility – Resulting metabolites are pharmacologically inactive

Enzymes mediating phase I & II metabolism Cytochrome P 450 (CYP) Oxidation Metabolism Flavin containing monooxygenase (FMO) Phase I (Oxidative Reactions) Phase II (Conjugative Reactions) Reduction Cytochrome P 450 reductase Hydrolysis Esterases UDPglucuronosyltransferases (UGT) Sulfotransferases (SULT)

Metabolism of Tamoxifen

Factors influencing metabolism • Liver function • Age • Gender • Smoking status & alcohol consumption • Genetics • Extent of protein binding • Concurrent drugs (Enzyme inhibition & induction)

Examples

Metabolic Enzyme Inhibition Enzyme inhibition If parent drug is pharmacologically active TOXICITY Decreased drug clearance Systemic accumulatio n of parent drug but less metabolites are formed If metabolites are pharmacologically active TREATMENT FAILURE

Example: Terfenadine & CYP 3 A 4 activity 60 mg terfenadine Only 6 ng/ml remains in the blood after metabolism (as prescribed) 60 mg terfenadine Erythromycin inhibits CYP 3 A 4 60 ng/ml in the blood (overdose) erythromycin

Metabolic Enzyme Induction Enzyme induction If parent drug is pharmacologically active TREATMENT FAILURE Increased drug Decreased clearance systemic level of parent drug & increased plasma level of metabolites If metabolites are pharmacologically active TOXICITY

Pharmacokinetics (PK) Absorption Metabolism Pharmacokinetics (PK) Excretion Distribution

Excretion • Irreversible loss of chemically unchanged compound (i. e. parent drug) – Usually hydrophilic or polar compounds • Organs involved: Kidney, lungs, skin, liver

Renal Excretion Net renal excretion = Filtration – Reabsorption + Secretion

Renal Excretion • Glomerular filtration – 20 to 25% of cardiac output, or 1. 1 L of blood per minute, goes to kidneys – Of this volume, 10 % is filtered at the glomerulus by the hydraulic pressure exerted by the arterial blood – Only unbound drug in plasma (concentration Cu) is filtered • Secretion – Active transport of drug from blood to lumen of nephron – Occurs predominantly in proximal tubule – Substances transported by the same system can compete with each other, which may affect their renal clearance

Renal Excretion • Tubular reabsorption – Usually an active process for many vital endogenous compounds e. g. vitamins, electrolytes, etc – Occurs by a passive process for most exogenous compounds including xenobiotics – Degree of reabsorption depends on drug properties, urine flow and urine p. H Renal clearance: volume of plasma passing through the kidney that is cleared of drug per unit time

Factors influencing renal excretion • Renal function • p. H of urine • Concurrent drugs • Genetics • Extent of protein binding

Summary • Pharmacokinetics describes how the body handles the drug. • It is quantitation of the time course of four process: absorption, distribution, metabolism and excretion (ADME) for a drug and its metabolites in the body. • Absorption refers to the transfer of drug from site of administration to site of measurement. – Various sites of administration may be classified as either intravascular or extravascular. – The plasma concentrations achieved can be controlled by the rate of drug administration (i. e. dose of drug and frequency of administration). • Distribution is the process of reversible transfer of a drug to and from the site of measurement, usually plasma, and the peripheral tissues. – It is mathematically described as volume of distribution (Vd) which refers to the volume of bodily fluid into which a drug dose appears to be distributed to account for its plasma concentration.

Summary • Elimination is the irreversible loss of drug from the site of measurement. – It involves two processes, excretion and metabolism. – Metabolism refers to the conversion of one chemical species to another. It generally refers to the conversion of drugs to more polar entities. – Excretion is the irreversible loss of chemically unchanged compound. – PK parameters to describe elimination include clearance (Cl) and elimination half-life (t 1/2). • Clearance (Cl) refers to the volume of fluid presented to the eliminating organ that is completely cleared of drug per unit time. • Elimination half-life (t 1/2) refers to the time taken for the concentration of the drug to fall by one half.

References • Clinical Pharmacokinetics and Pharmacodynamics: Concepts and Applications Malcolm Rowland, Thomas N Tozer • Concepts in Clinical Pharmacokinetics: A Self. Instructional Course Joseph T. Dipiro • Applied Biopharmaceutics & Pharmacokinetics (Fifth Edition) Leon Shargel, Susanna Wu-Pong, Andrew BC Yu

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