Use of In Vitro Drug Metabolism Data to Evaluate Metabolic Drug-Drug Interactions in Man: The Need for Quantitative Databases.
Rodrigues, A. David PhD; Winchell, Gregory A. PhD; Dobrinska, Michael R. PhD
Journal of Clinical Pharmacology.
41(4):368-373, April 2001.
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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, f,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.
(C)2001 SAGE Publications