Pharmacokinetics: Metabolism of Drugs Course Coordinator Jamaluddin Shaikh, Ph.D. School of Pharmacy, University of Nizwa Lecture-8 February 26, 2012

Pharmacokinetic Components

Drug Metabolism Drug metabolism is a process by which drugs are inactivated by living organisms, usually through specialized enzymatic systems Metabolism often converts lipophilic drugs into more readily excreted polar products Not all metabolic processes result in inactivation and drug activity is sometimes increased by metabolism Liver is the major site for drug metabolism, but specific drugs may undergo biotransformation in other tissues

Kinetics of Metabolism Two types of receptor kinetics: First-order kinetics Zero-order kinetics First-order Kinetics A constant fraction of the drug in the body is eliminated per unit time The rate of elimination is proportional to the amount of drug in the body The majority of drugs are eliminated in this way

First-order elimination 5 units/h Elimination rate 8 Plasma concentration 2.5 units/h 4 2 1.25 units/h 1 Time (h)

Zero-order Kinetics A constant amount of drug is eliminated per unit time This form of kinetics occur with several important drugs at high dosage concentrations, e.g., phenytoin, ethanol, theophylline Under this condition metabolizing enzymes are saturated by high free-drug concentration

Zero-order elimination 2.5 units/h Elimination time Plasma concentration 2.5 units/h 2.5 units/h Time (h)

Reactions of Drug Metabolism The kidney cannot efficiently eliminate lipophilic drugs that readily cross cell membranes and are reabsorbed in the distal tubules Therefore, lipid-soluble agents must first be metabolized in the liver using two general sets of reactions Phase 1 reaction Phase 2 reaction

Phase 1 Reaction Convert lipophilic molecules into polar molecules by introducing a polar functional group, such as -OH or -NH2 If the metabolites of phase 1 reactions are sufficiently polar, they may be readily excreted at this point CYP450 system is important for the metabolism and biotransformation of exogenous substances (drugs) Reaction can be fulfilled by amine oxidation (catecholamines), alcohol dehydrogenation (ethanol oxidation), and hydrolysis

Phase 2 Reaction It is a conjugation reaction If the metabolites of phase 1 reactions are not sufficiently polar, they undergo a subsequent conjugation reaction with endogenous substance, such as glucoronic acid, sulfuric acid, acetic acid, or an amino acid These conjugates are polar, and most often inactive Highly polar drug conjugates may then be excreted by the kidney Sites on drugs where conjugation reactions occur include -COOH, -OH, or NH2 groups,

Phase1 Vs Phase 2 Reaction Drug Derivative Conjugate Oxidation Hydroxylation Hydrolysis Conjugation Example Glucoronic acid Salicylic acid Glucoronide

Metabolism of Drugs at Intestine Important for drugs undergoing enterohepatic circulation Estradiol is excreted in bile as a glucoronide conjugate, loses glucoronic acid, as a result, free drug is available for reabsorption via the intestine Net effect of enterohepatic recirculation is that each bile salt is reused many times Enterohepatic Circulation

Presystemic Metabolism and First Pass Effects This is a phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced before it reaches the systemic circulation It is fraction of lost drug during the process of absorption which is generally related to the liver and gut wall It reduces the bioavailability of the drug

Factors Affecting Metabolism Genetic variation influenced on bioavailability CYP450 monooxygenases systems can vary with ethnicity Pathologic condition can influence drug metabolism, including kidney, liver or heart disease Physiological factors such as age can influence on drug metabolism

Enzyme Induction Enzyme induction is a process in which a drug induces (i.e. initiates or enhances) the expression of an enzyme There is a rise in CYP450 content and increased CYP450 reductase activity Size of liver and hepatic blood flow increases If two or more drugs are given simultaneously, then one substance that is an inducing agent accelerate the metabolism of other drugs

Enzyme Inhibition Enzyme inhibition can refer to the inhibition of the expression of the enzyme by another molecule Types of enzyme inhibition: competitive uncompetitive non-competitive partially competitive