Drug Metabolism and Disposition

Drug Metab Dispos (July 2010)

Drug Metabolism and Disposition is a crucial aspect of pharmacology and toxicology, focusing on the biochemical modification of pharmaceutical substances or xenobiotics (chemicals found in an organism that are not normally produced or expected to be present in it) by living organisms, primarily through specialized enzyme systems. This process affects the drugs' efficacy and toxicity, determining their duration and intensity of action.

Overview

Drug metabolism is an essential process for the elimination of drugs from the body and involves their conversion to more water-soluble compounds that can be excreted. The liver is the primary site for drug metabolism, although other organs such as the intestine, kidneys, and lungs also play significant roles. The process involves two main phases: Phase I (functionalization reactions) and Phase II (conjugation reactions).

Phase I Reactions

Phase I reactions involve the introduction or unmasking of functional groups on the drug molecule, such as -OH, -NH2, or -SH. These reactions are primarily carried out by the cytochrome P450 enzyme family and can result in either the activation or inactivation of the drug. Common Phase I reactions include oxidation, reduction, and hydrolysis.

Phase II Reactions

Phase II reactions involve the conjugation of the drug or its Phase I metabolites with endogenous substrates, such as glucuronic acid, sulfuric acid, acetic acid, or amino acids, leading to the formation of more water-soluble compounds. These reactions are catalyzed by transferase enzymes like UDP-glucuronosyltransferases, sulfotransferases, and glutathione S-transferases.

Factors Influencing Drug Metabolism

Several factors can influence the rate and extent of drug metabolism, including genetic polymorphisms, age, sex, diet, and the presence of other drugs. These factors can lead to interindividual variability in drug responses and are a major consideration in pharmacotherapy.

Clinical Significance

Understanding drug metabolism is crucial for the development of new drugs and the safe and effective use of existing ones. It helps in predicting drug interactions, side effects, and variations in drug response among different individuals. Moreover, the study of drug metabolism and disposition is fundamental in the assessment of the pharmacokinetic properties of drugs, including their absorption, distribution, metabolism, and excretion (ADME).

Research and Methods

Research in drug metabolism and disposition involves various in vitro and in vivo techniques. In vitro methods include the use of liver microsomes, hepatocytes, and recombinant enzymes, while in vivo studies typically involve animal models and clinical trials in humans. These studies help in identifying the metabolic pathways of drugs, the enzymes involved, and potential drug-drug interactions.