Drug Metabolism

Metabolism - conversion of pharmacologically active, lipid-soluble drugs into water-soluble and pharmacologically inactive metabolites

• Increased water solubility decreases the Vd for a drug, enhancing its renal excretion and occasionally GI elimination
• Without metabolism, highly lipid-soluble drugs would not undergo renal excretion and would circulate for years on end
• Not all metabolites are pharmacologically inactive - some are active or even more active then their precursor drug

Rate of Metabolism

• Determined by the concentration of drug at the site of metabolism, and by the intrinsic rate of the metabolism process
• Hepatic blood flow determines delivery and therefore concentration of drug at the site of metabolism
• Intrinsic rate of metabolism is determined by factors that influence enzyme activity - eg. genetics and enzyme induction
• First-order kinetics - a constant fraction of available drug is metabolized in a given time period
• Zero-order kinetics - capacity of metabolizing enzymes is exceeded resulting in metabolism of a constant amount of drug per unit time

• Occurs in alcohol, aspirin and phenytoin at therapeutic concentrations

Metabolism Pathways

• Oxidation
• Reduction
• Hydrolysis
• Conjugation
• Phase I reactions - oxidation/reduction/hydrolysis - increase a drug's polarity and prepare it for phase II reaction
• Phase II reactions - conjugation reactions in which a drug/metabolites are covalently linked with a highly polar molecule to become more water soluble to aid excretion
• Most drugs are metabolized by hepatic microsomal enzymes, but metabolism also occurs in plasma via Hofmann elimination/ester hydrolysis, and in lungs/kidneys/GI tract
• Drug metabolism was evolved to protect against ingestion of toxic alkaloids in plants
• Hepatic microsomal enzymes - principally located in hepatic smooth endoplasmic reticulum, but also found in kidneys, GI tract and adrenal cortex
• GI tract has considerable metabolizing activity:

• Cytochrome P-450 is found extensively in the GI tract, but is mostly found in the small intestine
• The kidneys also oxidize and conjugate drugs and endogenous substrates using P450 and phase II enzymes

Phase I Enzymes

• Enzymes responsible for phase I reactions include cytochrome P-450 enzymes, non-cytochrome P-450 enzymes and flavin-containing monooxygenase enzymes
• Cytochrome P-450 Enzymes:

• Membrane-bound heme proteins that catalyze metabolism of endogenous compounds
• 450 means that the absorption peak is at 450nm when combined with carbon monoxide
• Also known as the mixed function oxidase system or monooxygenases because it involves both oxidation and reduction steps
• The terminal oxidase in the electron transport scheme
• More than 50 CYP-450 enzymes have evolved and are named according to their sequence homology
• CYP-3A4 is the most abundant, and CYP-3A4/5 metabolise more than half of all currently available drugs
• CYP-2D6 is responsible for phase I reactions involving nearly 25% of all drugs
• Microsomal enzymes catalyse most oxidation/reduction and conjugation reactions leading to metabolism of drugs
• Rate of drug metabolism may vary sixfold due to genetics
• Enzyme induction: the unique feature of hepatic microsomal enzymes in which drugs or chemicals stimulate their activity

• Noncytochrome P-450 Enzymes:

• Catalyse conjugation and hydrolysis primarily, and to a lesser extent oxidation and reduction
• Principally found in liver, but also in GI tract and plasma
• All conjugation reactions except glucuronic acid are catalyzed by noncytochrome P-450 enzymes
• 1 in 2500 individuals are homozygous for "atypical cholinesterase which results in a dramatic prolongation in the effect of succinylcholine and mivacurium

• Flavin-Containing Monooxygenase Enzymes:

• Oxidise nitrogen/sulfur/phosphorus-containing compounds

Phase II Enzymes

• Glucuronosyltransferases - catalyse the covalent addition of glucuronic acid to a variety of endogenous and exogenous compounds to improve water solubility
• Glutathione-S-Transferase - primarily a defensive system for detoxification and protection against oxidative stress. Compound A nephrotoxicitiy in rats is attributed to GST-dependent activation
• N-Acetyl-Transferase - N-acetylation is a common phase II reaction for heterocyclic aromatic amines eg. isoniazid

Oxidative Metabolism

• Requires an electron donor (NAD) and molecular oxygen for their activity
• The oxygen molecule is split, with one atom of oxygen oxidizing each molecule of drug and the other oxygen being incorporated into a molecule of water
• Loss of electrons results in oxidation, whereas a gain of electrons results in reduction

Reductive Metabolism

• Reductive pathways of metabolism involve CYP-450 enzymes transferring electrons directly to a substrate eg. halothane

Hydrolysis - enzymes responsible for drug hydrolysis do not involve CYP-450. Glucuronide conjugate hydrolysis occurs in the GI tract.

Conjugation - glucuronic acid conjugation involves CYP-450 enzymes. Glucuronic acid comes from glucose, and when conjugated to a drug/metabolite makes it inactive and water soluble

• Glucuronide conjugates are rarely reabsorbed and are usually excreted in bile/urine
• Reduced conjugation occurs in neonates due to reduced microsomal enzyme activity. This increases the risk of hyperbilirubinemia causing bilirubin encephalopathy.