The cytochrome P450 enzyme system. A family with actions, reactions and interactions. Part 2

Large interindividual variability exists in the capacity to oxidise drugs in man. An important contributing factor is the occurrence of a genetically determined polymorphism of some enzymes of the microsomal cytochrome P450 (CYP) enzyme system. In addition, numerous environmental factors influence oxidative drug metabolising activity. For the oxidative metabolism of drugs a family of CYP enzymes is responsible, of which CYP2D6 CYP2C, CYP3A, CYP1A and CYP2E are important. The capacity of CYP2D6 and CYP2C19 is genetically determined, i.e. the rate of metabolism of compounds which are predominantly metabolised by these enzymes in a population exhibit a bimodal distribution (extensive and poor metabolisers). For the other CYP enzymes, also a larger interindividual variability exists, but a unimodal frequency distribution is observed in the metabolic rate of drugs metabolised by these enzymes. The capacity of the CYP enzymes is generally limited and some substrates exhibit a high affinity. This may lead to clinically important drug inhibition interactions. Examples of such interactions are discussed in this paper. Drug-drug interactions can be predicted preclinically by performing 'in vitro' studies with human microsomes, hepatocytes or purified enzymes to identify which enzyme is predominantly metabolising which drug. These results can be confirmed 'in vivo' in well designed drug-drug interaction studies with a carefully selected limited number of drug combinations