Advances in understanding drug metabolism and its contribution to variability in patient response

Recent advances in the understanding of the molecular biology and genetic variability of human drug metabolizing 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, whereas this knowledge has implications for therapeutics, appreciation and application in clinical practice have either been limited or yet to be realized. For example, the debrisoquine polymorphism was discovered 20 years ago, but controlled prospective studies to evaluate its clinical significance and pharmacoeconomic impact are few. Come the millennium it will be seen to what extent traditional therapeutic drug monitoring, involving the measurement of specific plasma drug concentrations, may be complemented or replaced by more general phenotyping or genotyping screens for human drug metabolizing enzymes.