In vitro drug-drug interaction studies with febuxostat, a novel non-purine selective inhibitor of xanthine oxidase: plasma protein binding, identification of metabolic enzymes and cytochrome P450 inhibition.
1. The potential for drug-drug interactions with febuxostat was examined in the following three in vitro systems: the characteristics of the binding of febuxostat to human plasma proteins; identification of the cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes participating in the metabolism of febuxostat; and the potential inhibitory effects of febuxostat on typical CYP reactions. 2. The results have shown that the presence of ibuprofen or warfarin did not change the plasma protein binding of febuxostat, and that febuxostat did not influence the plasma protein binding of ibuprofen or warfarin. These results indicate that there is little possibility that febuxostat causes a drug-drug interaction by binding to albumin. 3. The UGT 1 and 2 families were involved in the glucuronidation, and several CYPs participated in the metabolism of febuxostat, suggesting that there is little possibility that the blood concentration of febuxostat varies widely even if febuxostat is concomitantly administered with drugs that inhibit CYP or UGT enzyme. Examination of the inhibitory effect of febuxostat on CYP enzymes suggests that febuxostat minimally inhibits the activities of any CYP. 4. The results demonstrate that febuxostat is a novel anti-hyperuricaemia drug with low drug-drug interaction potential in clinical use.
Mukoyoshi
M
M
Pharmaceutical Analysis & Pharmacokinetics Research Department, Tokyo, Japan. m.mukoyoshi@teijin.co.jp
Nishimura
S
S
Hoshide
S
S
Umeda
S
S
Kanou
M
M
Taniguchi
K
K
Muroga
H
H
D001798:Blood Proteins / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology*; D000069465:Febuxostat; D014453:Glucuronosyltransferase / Q000378:metabolism; D006801:Humans; D007052:Ibuprofen / Q000008:administration & dosage; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D013844:Thiazoles / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology*; D014859:Warfarin / Q000008:administration & dosage; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*
D001798:Blood Proteins; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D013844:Thiazoles; D000069465:Febuxostat; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; D014969:Xanthine Oxidase; D014453:Glucuronosyltransferase; D007052:Ibuprofen