Genotyping and phenotyping the cytochrome p-450 enzymes

With estimates of the percentage of pharmaceuticals that are subject to metabolism by the cytochrome P-450 enzymes (CYPs) in excess of 80%, the relative activities of these enzymes in various subpopulations and even in individual patients can have important ramifications in matters ranging from dose selection to prediction of toxicity to suitability of a new chemical entity (NCE) for continued drug development. The interindividual variation in CYP activities can be profound, and the differences may be due to environmental/physiologic factors, genetic factors, or both. With regard to the process of drug development, it would be useful to know as early in the development process as possible which CYPs are likely to process a NCE, the likely interindividual variation in the processing of a NCE by CYPs, which CYP activities are likely to be altered by a NCE, and the magnitude by which CYP activity is likely to be altered by a NCE. The latter two, in particular, will be useful in predicting drug interactions between the NCE and currently available drugs. For purposes of establishing treatment regimens that are maximally effective and minimally toxic, it follows that advance knowledge of probable CYP activities could be helpful. To the extent that phenotypic expression of CYP activity corresponds to CYP genotype, it may be possible a priori to design optimized therapeutic regimens for selective CYP substrates based on knowledge of a patient's CYP genotype. Because the expression of CYP activity is determined predominantly by prevailing environmental/physiologic conditions, tailoring drug therapy to meet individual patient needs can require knowledge of a patient's CYP phenotype. Strategies for genotyping and phenotyping CYP-450 activity are discussed with special attention paid to in vivo phenotyping methods.