Drug‐Metabolising Enzymes: Genetic Polymorphisms

Abstract Polymorphism in drug‐metabolising enzymes is of great importance for interindividual differences in drug therapy. Variant genes causing increased, decreased or abolished drug metabolism influences the drug response and risk for adverse drug reactions. The genetic alterations include single‐nucleotide polymorphisms, ins/del and gene copy number variations. Of particular importance are the cytochrome P450 enzymes responsible for the metabolism of the majority of clinically important drugs. This variability is now emphasised during drug development and of importance for routine drug prescription. Several different drugs contain pharmacogenomic labels where genotyping before prescription is mandatory or recommended. Predictive genotyping of drug‐metabolising genes can thus help to design individualised, safer and more efficient drug therapies. Key Concepts: The majority of drug metabolism is carried out by cytochrome P450 enzymes. The polymorphic cytochrome P450 enzymes account for 40% of the phase I drug metabolism. The major phenotypes with respect to drug metabolism are poor metabolisers (PMs), intermediate metabolisers (IMs), extensive metabolisers (EMs) and ultrarapid metabolisers (UMs). There are large interethnic differences in the drug metabolism caused by genetic factors. The toxicity of some anticancer drugs, and antibiotics can be predicted by the occurrence of particular genes encoding drug‐metabolising enzymes. The effective dose of clopidogrel, warfarin, tricyclic antidepressants, tamoxifen and some antipsychotics is determined by the P450 polymorphism. Irenotecan and mercaptopurine toxicity is dependent on UGT1A1 and TPMT polymorphism, respectively. 85% of the pharmacogenomic drug labels refer to genes encoding drug‐metabolising enzymes, in particular cytochrome P450.