In-vitro Biotransformation of BOF-4272, a Sulphoxide-containing Drug, in Rats, Mice and Cynomolgus Monkeys: Sex and Species Differences

• Published in: Pharmacy and Pharmacology Communications 1999-11, Vol.5 (11), p.645-651
• Main Authors: NAITO, SHINSAKU, NISHIMURA, MASUHIRO, YOSHITSUGU, HIROKI
• Format: Article
• Language: English
• ISSN: 1460-8081; 2042-7158
• DOI: 10.1211/146080899128734307

BOF‐4272 is a new drug intended for the treatment of hyperuricemia. In this study we describe in‐vitro sex and species differences in the biotransformation of BOF‐4272 in male and female rats, male mice, and male cynomolgus monkeys. Biotransformation was determined by identifying the metabolites found in liver S9 incubation mixtures after addition of BOF‐4272, BOF‐4269 (8‐(3‐methoxy‐4‐phenylsulphenyl‐phenyl) pyrazolo[1,5‐a]‐1,3,5‐triazine‐4(1H)‐one), M‐1 (8‐[3‐methoxy‐4‐(4‐hydroxyphenyl‐sulphenyl)phenyl] pyrazolo[1,5‐a]‐1,3,5‐triazine‐4(1H)‐one), or M‐3 ((±)‐2‐hydroxy‐8‐(3‐methoxy‐4‐phenylsulphenylphenyl) pyrazolo[1,5‐a]‐1,3,5‐triazine‐4(1H)‐one). M‐4 ((±)‐2‐hydroxy‐8‐(3‐methoxy‐4‐phenylsulphinylphenyl) pyrazolo[1,5‐a]‐1,3,5‐triazine‐4(1H)‐one), was the main metabolite identified in the S9 incubation mixture after addition of BOF‐4272 in both male and female rats, but biotransformation of BOF‐4272 to M‐4 was greater in female rats. BOF‐4272 was metabolized mainly to M‐4 in rat and mouse liver, and was metabolized to M‐6 ((±)‐2‐hydroxy‐8‐(3‐methoxy‐4‐phenylsul‐phonylphenyl) pyrazolo[1,5‐a]‐1,3,5‐triazine‐4(1H)‐one) via M‐4 in cynomolgus monkey liver. Biotransformation of BOF‐4269 to M‐5 (2‐hydroxy‐8‐[3‐methoxy‐4‐(4‐hydroxy‐phenylsulphenyl)phenyl] pyrazolo[1,5‐a]‐1,3,5‐triazine‐4(1H)‐one) via M‐1 or M‐3, may be the major metabolic pathway in male and female rats. Biotransformation of BOF‐4269 to M‐4 via BOF‐4272 may be the major pathway in female rats. Biotransformation of BOF‐4269 to M‐5 via M‐1 is the major pathway in mice, and biotransformation from BOF‐4269 to M‐5 via M‐3 is the major pathway in cynomolgus monkeys. These results indicate sex and species differences in the metabolic pathways involved in the biotransformation of BOF‐4272.