Role of cytochrome P450 enzymes in drug-drug interactions.
Many adverse drug-drug interactions are attributable to pharmacokinetic problems and can be understood in terms of alterations of P450-catalyzed reactions. Much is now known about the human P450 enzymes and what they do, and it has been possible to apply this information to issues related to practical problems. A relatively small subset of the total number of human P450s appears to be responsible for a large fraction of the oxidation of drugs. The three major reasons for drug-drug interactions involving the P450s are induction, inhibition, and possibly stimulation, with inhibition appearing to be the most important in terms of known clinical problems. With the available knowledge of human P450s and reagents, it is possible to do in vitro experiments with drugs and make useful predictions. The results can be tested in vivo, again using assays based on our knowledge of human P450s. This approach has the capability of not only improving predictions about which drugs might show serious interaction problems, but also decreasing the number of in vivo interaction studies that must be performed. These approaches should improve with further refinement and technical advances.
Guengerich
F P
FP
Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA.
D000818:Animals; D001628:Beverages; D001665:Binding Sites; D002927:Cimetidine / Q000378:metabolism; D002957:Citrus; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004347:Drug Interactions; D004997:Ethinyl Estradiol / Q000378:metabolism; D018565:Food-Drug Interactions; D006801:Humans; D006899:Mixed Function Oxygenases / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D016593:Terfenadine / Q000378:metabolism
D065607:Cytochrome P-450 Enzyme Inhibitors; D004364:Pharmaceutical Preparations; D004997:Ethinyl Estradiol; D016593:Terfenadine; D002927:Cimetidine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A