THE USE OF INVITRO METABOLISM STUDIES IN THE UNDERSTANDING OF NEW DRUGS

In vitro models derived from various animal species are routinely used for the evaluation of pharmacological potency and toxicological poten tial of new drug candidates. It is well known that metabolism of the d rug molecule often contributes to the efficacy and toxicity observed i n vivo. In vitro metabolism studies conducted in biological matrixes r anging from intact organ, tissue slice to subcellular fraction offer t he advantage of reduced complexity of the study system, and allow the evaluation of intrinsic metabolic potential or mechanism with respect to a specific reaction. In addition, in vitro systems derived from var ious animal species offer the possibility of comparing metabolic pathw ays among species, including humans, before a compound can be tested c linically. Two areas of particular interest for the use of in vitro st udies in the understanding of new drugs are 1) the relationship of met abolic pathway and pharmacodynamics and 2) the prediction of drug inte raction potential in humans. To illustrate these aspects, I review met abolism studies on losartan, an angiotensin-II receptor antagonist cur rently in phase-III clinical development for hypertension, and cyclosp orin A, a widely prescribed immunosuppressant.