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.

Photochemical mutagen formation from aerobically treated night-soil effluent and the contributive substances.

Effluents from a night-soil treatment plant, where night-soil was aerobically treated by an activated sludge process, were irradiated with a UV lamp excluding short wavelengths less than 300 nm as a model of exposure to sunlight and the mutagenicities of the ethylacetate extracts from the irradiated effluents were assayed using Salmonella typhimurium TA98. The extracts exhibited mutagenicity toward S. typhimurium TA98 in the absence of rat liver S9 fraction only when the effluents were fortified with nitrite ion (more than 6 ppm) by over aeration or by artificial addition of nitrite, indicating that a limiting factor for mutagen formation is nitrite ion concentration. Nine organic-N-containing compounds as models of the organic components in the effluent were also irradiated and direct-acting potent mutagens were found to be produced from such compounds having indole moiety as indole, oxindole, tryptophan and tryptamine.