Pharmacology I BMS 242 Lecture 4 Pharmacokienetic Principles

Pharmacology I BMS 242 Lecture 4 Pharmacokienetic Principles (3&4): Drug Metabolism and Excretion [Elimination] Dr. Aya M. Serry 2016

Definition Pharmacokinetics ABSORPTION METABOLISM What body does to the Drug DISTRIBUTION EXCRETION

III & IV. Elimination of the drug DISTRIBUTION ABSORPTION Drug Blood Stream At the site of administration Site of Action Elimination Excretion Metabolism

III & IV. Elimination of the drug • Drug Elimination is the irreversible removal of the parent drugs from the body • Drug biotransformation and drug excretion are the two processes responsible for the elimination of the parent drug from the blood Elimination Excretion Metabolism (Biotransformation)

III. Drug Metabolism • Drug metabolism is the chemical modification of drugs with the overall goal of getting rid of the drug • Enzymes are typically involved in metabolism • Metabolism always results in drug metabolites that are more polar (water soluble) than the parent drug • Making drugs more polar makes them more readily excreted from the body by the principle organ of excretion, the kidney Drug Metabolism More water soluble (polar) Excretion

III. Drug Metabolism Sites of Drug Metabolism • Metabolism occurs in many tissues. e. g. brain, kidney, lungs • But mostly in the liver

III. Drug Metabolism Consequences Of Metabolism • Drug metabolism != Drug inactivation • The metabolite may have: § Equal activity to the drug § No or reduced activity § Increased activity (Prodrugs**) § Toxic properties, not seen with the parent drug ** A Prodrug is an inactive or partially active drug that is changed via metabolism into an active drug. Example: Heroin is metabolized by esterase enzyme to the active morphine

III. Drug Metabolism The Most Important metabolic Enzymes • Cytochrome P 450 (CYPs); is a large and diverse group of enzymes that catalyze the oxidation of organic substances • CYPs are the major enzymes involved in drug metabolism, accounting for about 75% of the total metabolism • Most drugs undergo deactivation by CYPs, either directly or by facilitated excretion from the body • Also, many substances are bioactivated by CYPs to form their active compounds

Phases of Metabolism q Phase I: Phase I reactions function to convert lipophilic molecules into more polar molecules by introducing or unmasking polar functional groups such as -OH, -NH 2, or -SH. However, Some Phase I products are still not eliminated rapidly, and hence undergo Phase II reactions q Phase II: This phase consists of conjugation reactions. Many Phase I metabolites are too lipophilic to be retained in the kidney tubules. A conjugation reaction with an endogenous compound such as glucuronic acid or sulfuric acid, results in polar, usually more water-soluble compounds q Reversal of order of the phases: Not all drugs undergo Phase I and II reactions in that order. The reverse can happen

IV. Drug Elimination • Removal of a drug from the body occurs via a number of routes, the most important being through the kidney into the urine • Other routes include the bile, intestine, lung, or milk in nursing mothers • A patient in renal failure may undergo renal dialysis, which removes small molecules such as drugs and toxins

ADME - Summary