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Reductive Isoxazole Ring Opening of the Anticoagulant Razaxaban Is the Major Metabolic Clearance Pathway in Rats and Dogs

Pharmaceutical Candidate Optimization (D.Z., N.R., H.Z., L.L., G.L.S., K.H.), Radiochemistry (S.-Y.C., S.J.B.), Discovery Chemistry (M.Q., P.Y.S.L.), Drug Safety Evaluation (L.M.P.), and Discovery Biology (R.M.K.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey

Razaxaban is a selective, potent, and orally bioavailable inhibitor of coagulation factor Xa. The molecule contains a 1,2-benzisoxazole structure. After oral administration of [¹⁴C]razaxaban to intact and bile duct-cannulated rats (300 mg/kg) and dogs (20 mg/kg), metabolism followed by biliary excretion was the major elimination pathway in both species, accounting for 34 to 44% of the dose, whereas urinary excretion accounted for 3 to 13% of the dose. Chromatographic separation of radioactivity in urine, bile, and feces of rats and dogs showed that razaxaban was extensively metabolized in both species. Metabolites were identified on the basis of liquid chromatography/tandem mass spectrometry and comparison with synthetic standards. Among the 12 metabolites identified, formation of an isoxazole-ring opened benzamidine metabolite (M1) represented a major metabolic pathway of razaxaban in rats and dogs. However, razaxaban was the major circulating drug-related component (>70%) in both species, and M1, M4, and M7 were minor circulating components. In addition to the in vivo observations, M1 was formed as the primary metabolite in rat and dog hepatocytes and in the rat liver cytosolic fraction. The formation of M1 in the rat liver fraction required the presence of NADH. Theses results suggest that isoxazole ring reduction, forming a stable benzamidine metabolite (M1), represents the primary metabolic pathway of razaxaban in vivo and in vitro. The reduction reaction was catalyzed by NADH-dependent reductase(s) in the liver and possibly by intestinal microflora on the basis of the recovery of M1 in feces of bile duct-cannulated rats.