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-inhibitor pair, the magnitude of the interaction will depend on the potency of the inhibitor (inhibition constant, Ki) the concentration of the inhibitor available for inhibition ([I]), the fraction of the substrate dose metabolized by CYP (fm), and the fraction of the CYP-dependent metabolism catalyzed by the inhibited CYP form (e.g., fm,CYP3A4). While progress is being made toward our understanding of the factors necessary for predictions of [I]/Ki in vivo, it is evident that there is a need for quantitative databases that contain in vitro (e.g., Ki, fm,CYP3A4) and in vivo pharmacokinetic/absorption-distribution-metabolism-excretion (PK/ADME) data (e.g., fm) for a large number of marketed drugs. Ultimately, such databases would allow one to integrate all of the data necessary for the prediction of drug-drug interactions and permit the rational evaluation of new drug entities.
Rodrigues
A D
AD
Department of Drug Metabolism, Merck Research Laboratories, Sumneytown Pike, West Point, PA 19486-0004, USA.
Winchell
G A
GA
Dobrinska
M R
MR
D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D016208:Databases, Factual; D015195:Drug Design; D004347:Drug Interactions; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D010599:Pharmacokinetics; D012680:Sensitivity and Specificity
D007527:Isoenzymes; D003577:Cytochrome P-450 Enzyme System