Pharmacogenetic Variation in Drug Oxidizing CYPs: Impact on Drug Therapy, Drug Safety and Drug Interactions

Cytochromes P450 (CYPs) are multifunctional enzymes that are active in the oxidative metabolism of many drugs and play a dominant role in the elimination of drugs from the body. Pharmacokinetic interactions may arise when the biotransformation and elimination of a drug are impaired by coadministered drugs. Thus, drugs may compete for biotransformation by a common CYP. Adverse drug reactions, including toxicity, can occur if elimination is dependent on a CYP that exhibits defective gene variants. Thus, the genetic makeup of the individual is a major influence on the duration of drug action, as well as drug efficacy and safety. This review summarises recent information on the mechanisms of drug-drug interactions that are due to impaired CYP function and also outlines the impact of aberrant CYP genes on drug biotransformation. Evidence is presented that CYP pharmacogenetics affects the propensity for certain drug-drug interactions. Thus, the future safe use of drug combinations in patients may require genotyping and phenotyping of individuals before the commencement of therapy. Identification of subjects who metabolise drugs in a different fashion from the general population should minimise the impact of pharmacogenetic variation on drug pharmacokinetics. Keywords: Cytochrome P450, P450 pharmacogenetics, pharmacokinetic interactions, CYP allele, reversible inhibition, irreversible inhibition, polymorphism