Prediction of the metabolic interaction of nateglinide with other drugs based on in vitro studies.
Nateglinide is an antidiabetic agent metabolized by CYP2C9 and CYP3A4; hence inhibitors of these CYP isozymes may interact with nateglinide. There are, however, only limited in vitro data on how to predict drug-drug interactions in vivo. We examined the effects of 18 drugs that may be prescribed together with nateglinide (metformin, buformin, aspirin, gemfibrozil, simvastatin, pioglitazone, rosiglitazone, carbamazepine, clarithromycin, gliclazide, clofibrate, fluconazole, bezafibrate, phenylbutazone, nifedipine, famotidine, ibuprofen and miconazole) on the conversion of nateglinide to its major metabolite (N-[trans-4-(1-hydroxy-1-methylethyl)-cyclohexanecarbonyl]-D-phenylalanine) using human liver microsomes. Eight compounds showed a<50% inhibitory effect and we estimated the K(i) values for the remaining 10 compounds. Except for fluconazole and miconazole, 1+I(in, max, u)/K(i) calculated from the K(i) values, was approximately 1 and thus the possibility of a drug-drug interaction was considered low. The value for fluconazole suggested the risk of interaction and agreed with the results of clinical studies in which the AUC of nateglinide increased by 48% when it was co-administered with fluconazole. The present study showed that nateglinide metabolism would hardly be affected by the drugs used in this study, except for miconazole and fluconazole that are potent inhibitors of multiple isoforms of CYPs.
Takanohashi
Toshiyuki
T
Pharmaceutical Company, Ajinomoto Co., Inc., Kawasaki-ku, Kawasaki, Japan. toshiyuki_takanohash@ajinomoto.com
Koizumi
Tomonori
T
Mihara
Ryuichi
R
Okudaira
Kazuho
K
D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D001711:Biotransformation; D003510:Cyclohexanes / Q000378:metabolism*; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism*; D066298:In Vitro Techniques; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D008954:Models, Biological; D000077715:Nateglinide; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000378:metabolism
D003510:Cyclohexanes; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D000077715:Nateglinide; D010649:Phenylalanine; D003577:Cytochrome P-450 Enzyme System; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human