Clinical aspects of polymorphic drug metabolism

Recent advances in our understanding of the molecular biology and genetic variability of human drug metabolising enzymes, particularly cytochromes P450, have contributed immensely towards clarifying the pharmacokinetics and pharmacodynamics of many existing drugs, and are increasingly important in the development of new chemical entities. However, while this knowledge has implications for therapeutics, appreciation and application in clinical practice has either been limited or yet to be realised. For example, the debrisoquine polymorphism was discovered 20 years ago, but controlled prospective studies to evaluate its clinical significance are few. The clinical implications of genetic polymorphisms in drug metabolism, as they relate to drug toxicity, therapeutic failure and susceptibility to diseases, are reviewed briefly with specific reference to CYP2D6.