Use of in vitro drug metabolism data to evaluate metabolic drug-drug interactions in man: The need for quantitative databases

It has become widely accepted that metabolic drug-drug interactions can be forecast using in vitro cytochrome P450 (CYP) data. For any CYP form-inhibi tor pair, the magnitude of the interaction will depend on the potency of th e inhibitor (inhibition constant, K-i), the concentration of the inhibitor available for inhibition ([I]), the fraction of the substrate dose metaboli zed by GYP (f(m)), and the fraction of the CYP-dependent metabolism catalyz ed by the inhibited CYP form (e.g., f(m,CYP3A4)). While progress is being m ade toward our understanding of the factors necessary for predictions of [I ]/K-i in vivo, it is evident that there is a need for quantitative database s that contain in vitro (e.g., K-i,f(m),(CYP3A4)) and in vivo pharmacokinet ic/absorption-distribution-metabolism-excretion (PK/ADME) data (e.g., f(m)) for a large number of marketed drugs. Ultimately, such databases would all ow one to integrate all of the data necessary for the prediction of drug-dr ug interactions and permit the rational evaluation of new drug entities. (C ) 2001 the American College of Clinical Pharmacology.