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Western University
Pharmacology 2060A/B
Angela Nissen

Module 4 – Pharmacokinetics (Metabolism) 4.1 Drug Metabolism • Metabolism is the enzyme mediated alteration of a drug’s structure • Metabolism is also referred to as biotransformation • Sites of drug metabolism include:  • • Why do we need drug metabolism o Drug metabolism is important in humans to protect us from a number of  environmental toxins as well as synthesize essential endogenous  molecules o A summary of common exogenous toxins that drug metabolism protects us  from are summarized below  similarly essential endogenous molecules synthesized by drug  metabolizing enzymes are shown • o note that even things like vegetables considered to be healthy would be toxic if we didn’t have enzyme to process them • Therapeutic Consequences of Drug Metabolism o Increase water solubility of drugs promote their excretion  Lipophilic ▯ hydrophilic o Inactivate drugs  Active ▯ inactive o Increase drug effectiveness  Active ▯ more active o Activate prodrugs (prodrugs are inactive until metabolized)  Prodrug (inactive) ▯ active drug o Increase drug toxicity  Non toxic ▯ toxic 4.2 Kinetics of Drug Metabolism • First Order o In most clinical situations the concentration of drug is much lower than the metabolic capacity of the body  In these situations drug metabolism displays 1 order kinetics o In 1 order kinetics drug metabolism is directly proportional to the concentration of free drug o Aconstant fraction of drug is metabolized per unit time o o in the figure, 1 order kinetics  concentration decreases faster when there are higher drug concentrations than at the end when concentrations are low  much more enzyme than there is drug in 1 order metabolism • Zero Order o In zero order kinetics, the plasma drug concentration is much higher than the metabolic capacity of the body o Drug metabolism is constant over time o Constant amount of drug is metabolized per unit time o ETHANOL o o metabolism is independent of drug concentration o much more drug than enzyme 4.3 First Pass Metabolism • PO drugs may undergo significant metabolism prior to entering the systemic circulation o First pass metabolism • Occur via: o Hepatocytes in liver o Intestinal enterocytes o Stomach o Intestinal bacteria • • result: decreased amount of parent drug in systemic circulation • Extraction Ratio o Amount of metabolism on the first pass through the liver can greatly determine a drug’s availability o Drugs are characterized as having high or low extraction ratio (ER) depending on how much metabolism occurs on the first pass through the liver o High ER Drugs  Low oral availability (1-20%)  PO doses are usually much higher than IV doses (to compensate for high first metabolism)  Small changes in hepatic enzyme activity produce large changes in bioavailability  First pass through liver results in high metabolism rate  Very susceptible to drug-drug interactions o Low ER Drugs  Have high oral bioavailability (>80%)  PO doses are usually similar to IV doses  Small changes in hepatic enzyme activity have little effect on bioavailability  Not very susceptible to drug-drug interactions  Take many passes through liver via systemic circulation before they are completely metabolized  Barely metabolized when passed through liver 4.4 Types of Drug Metabolism • Drug metabolism is broadly divided into 2 phases (phase I metabolism and phase II metabolism • Phase I Metabolism o Convert lipophilic drugs to more polar molecules by introducing or unmasking polar functional groups (ex. hydroxyl (-OH) or amine (-NH )2 o Involves oxidation, reduction and hydrolysis reactions o Mediated by cytochrome P450 enzymes, esterases and dehydrogenases o Metabolites formed can be more active, less active or equally active as the parent drug o Occurs in SER • Phase II Metabolism o Increase the polarity of lipophilic drugs by conjugation reactions (addition of large water soluble molecule to drug)  Conjugation rxn - Making them more hydrophilic o Conjugates include glucoronic acid (a sugar), sulfate (-SO4), acetate or amino acids (ex. Glycine) o Occurs in cytosol o Metabolites are less active than parent drug o Exception – Morphine  Morphine 6-glucoronide (metabolite of morphine) is more potent analgesic (pain reliever) than morphine • • Intracellular Site of Drug Metabolizing Enzymes o Phase I – phase I drug metabolizing enzymes are localized to the SER o Phase II – phase II drug metabolizing enzymes are localized predominantly in the cytosol of the cell with the exception of glucoronidation which is localized to the SER 4.5 Cytochrome P450 Drug Metabolizing Enzymes • CYPs (Cytochrome P450) are a large family of drug metabolizing enzmes • Predominant phase I drug metabolizing enzyme system • Majority drug metabolism in the body is performed by hepatic CYP enzyme • CYPs oxidize drugs o By inserting one atom of oxygen into the drug molecule producing water as a byproduct • Drug + O + NADPH + H → Drug + + H 0 + NADP + 2 oxidized 2 • There are 12 families of CYPs with 3 accounting for the majority of drug metabolism • Malnutrition can decreased CYP activity o These enzymes require protein, iron, folic acid and zinc for full activity • Nomenclature: o CYP3A4 metabolizes the largest fraction of currently marketed drugs  Approximately 50% • 4.6 Phase II Drug Metabolizing Enzymes • Phase II drug metabolizing enzymes include: 1. UDP-glucoronosyltransferases (UGTs) 2. Sulfotransferases (SULTs) 3. Glutathione S Transferase
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