Human drug metabolism and the cytochromes P450: Application and relevance of in vitro models

The cytochromes P450 (CYPs) constitute a superfamily of hemoprotein enzymes that are responsible for the biotransformation of numerous xenobiotics, in cluding therapeutic agents. Studies of the biochemical and enzymatic proper ties of these enzymes and their molecular genetics and regulation of gene e xpression and activity have greatly enhanced our understanding of several a spects of clinical pharmacology such as pharmacokinetic variability, drug t oxicity, and drug interactions. This review evaluates the major human hepat ic drug-metabolizing CYP enzymes and their clinically relevant substrates, inhibitors, and inducers, Also discussed are the molecular bases and clinic al implications of genetic polymorphisms that affect the CYPs. Much of the information on the specificity of substrates and inhibitors of the CYP enzy mes is derived from in vitro studies using human liver microsomes and heter ologously expressed CYP enzymes. These methods are discussed, and guideline s are provided for designing enzyme kinetic and reaction phenotyping studie s using multiple approaches. The strengths, weaknesses, and discrepancies a mong the different approaches are considered using representative examples. The mathematical models used in predicting the pharmacokinetic clearance o f 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.