Biotransformation of the xanthine oxidase inhibitor BOF-4272 and its metabolites in the liver and by the intestinal flora in rat

1. BOF-4272, (+/-)-8-(3-methoxy-4-phenylsulfinylphenyl) pyrazolo1,5-a]-1,3,5-triazine-4(1H)-one), is a new drug intended for the treatment of hyperuricaemia. 2. This paper describes the detailed biotransformation of BOF-4272 and its metabolites in the liver and by the intestinal flora in rat. 3. Only the sulphoxide metabolite (M6) was detected in plasma in small amounts after the intravenous administration of M4 (hydroxy-BOF-4272) and in culture medium after the addition of M4. 4. Only M3 (the sulphide metabolite of M4) was detected in faeces, and its amount was approximately 50% of the administered dose within 1 day after the intravenous administration of M4. 5. These findings suggest that M4, which is excreted in the bile, is metabolized mainly to M3 (the corresponding sulphide of M4) by the intestinal flora in rat, whereas little M4 is metabolized to the sulphoxide (M6) in the rat liver. 6. M2, which is the demethylated form of BOF-4269, was detected in faeces after the oral administration of BOF-4272 to rat in which the common bile duct was cannulated, suggesting that BOF-4272 is metabolized to BOF-4269 and then to M2 by the intestinal flora. 7. These findings suggest that in rat the sulphoxide of BOF-4272 and its metabolites are demethylated and reduced by the intestinal flora, with other types of biotransformation occurring in the liver.