Human Drug Metabolism and the Cytochromes P450: Application and Relevance of In Vitro Models

Abstract

The cytochromes P450 (CYP s) constitute a superfamily of hemoprotein enzymes that are responsible for the biotransformation of numerous xenobiotics, including therapeutic agents. Studies of the biochemical and enzymatic properties of these enzymes and their molecular genetics and regulation of gene expression and activity have greatly enhanced our understanding of several aspects of clinical pharmacology such as pharmacokinetic variability, drug toxicity, and drug interactions. This review evaluates the major human hepatic drug‐metabolizing CYP enzymes and their clinically relevant substrates, inhibitors, and inducers. Also discussed are the molecular bases and clinical implications of genetic polymorphisms that affect the CYPs. Much of the information on the specificity of substrates and inhibitors of the CYP enzymes is derived from in vitro studies using human liver microsomes and heterologously expressed CYP enzymes. These methods are discussed, and guidelines are provided for designing enzyme kinetic and reaction phenotyping studies using multiple approaches. The strengths, weaknesses, and discrepancies among the different approaches are considered using representative examples. The mathematical models used in predicting the pharmacokinetic clearance of a drug from in vitro estimates of intrinsic clearance and the principles of quantitative in vitro‐in vivo scaling of metabolic drug interactions are also discussed.