Factors confounding the successful extrapolation of in vitro CYP3A inhibition information to the in vivo condition.
For the most part, the majority of adverse drug-drug interactions, which are pharmacokinetic in origin, can be understood in terms of alterations of cytochrome P450-catalyzed reactions. Much is known about the human P450 enzymes, and in many cases it is possible to apply this information to clinically related issues. Of the relatively small subset of the total number of human P450s, CYP3A4 appears to be responsible for the largest fraction of the drug oxidation reactions. As a consequence many important drug-drug interactions observed in the clinic are associated with drugs which are principally metabolized by CYP3A4. The two major reasons for drug-drug interactions involving CYP3A4 are induction and inhibition, with inhibition appearing to be the more important in terms of known clinical problems. Fortunately, with the available knowledge of human P450s and in vitro reagents, it is possible to do experiments with drugs to predict the in vivo condition. The goal of these studies is not only to improve predictions about which drugs might show serious P450 interaction problems, but also to decrease the number of in vivo interaction studies that must be performed in drug development. The focus of the current report is to describe some of the confounding factors associated with in vitro drug inhibition studies and the impact of these issues on in vitro/in vivo extrapolations.
Wienkers
Larry C
LC
Global Drug Metabolism, Pharmacia, 301 Henrietta St., Kalamazoo, MI 49009, USA. larry.c.wienkers@am.pnu.com
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism* / Q000502:physiology; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000502:physiology; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D010089:Oxidoreductases, N-Demethylating