Abstract
The cytochrome P450 (P450) enzymes are the predominant enzyme system involved in human drug metabolism. Alterations in the expression and/or activity of these enzymes result in changes in pharmacokinetics (and consequently the pharmacodynamics) of drugs that are metabolized by this set of enzymes. Apart from changes in activity due to drug-drug interactions (by P450 induction or inhibition), the P450 enzymes can exhibit substantial interindividual variation in basal expression and/or activity, leading to differences in rates of drug elimination and response. This interindividual variation can result from a myriad of factors including genetic variation in the coding region, genetic variation in the promoter region, variation in transcriptional regulators, alterations in micro-RNA that impact P450 expression, and ontogenic changes due to exposure to xenobiotics during the developmental and early post-natal periods. Other than administering a probe drug or cocktail of drugs to obtain the phenotype or conducting a genetic analysis to determine genotype, methods to determine inter-individual variation have been limited. Phenotyping via a probe drug requires exposure to a xenobiotic, and genotyping is not always well correlated with phenotype, making both methodologies less than ideal. This manuscript describes recent work evaluating the impact of some of these factors on interindividual variation in human P450-mediated metabolism and the potential utility of endogenous probe compounds to assess rates of drug metabolism among individuals.
- cytochrome P450
- gene regulation/transcription
- metabolomics
- ontogeny/development/ageing
- pharmacogenetics/pharmacogenomics
- The American Society for Pharmacology and Experimental Therapeutics