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

Abstract

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.