Metabolism of the bisphosphonate ester U-91502 in rats

The major metabolites of the bisphosphonate ester U-91502 were isolated from the bile and urine of male Sprague-Dawley rats and identified by NMR and MS. Bile duct-exteriorized and taurocholate-supplemented rats received single oral doses of 10-140 mg/kg of labeled U-91502. Analysis of radioactivity in bile, urine, and feces showed that U-91502-related radioactivity was rapidly excreted, predominantly in bile, achieving peak concentrations in bile of 1250 +/- 622 micrograms-eq/g during first 3 hr after a 10 mg/kg dose. The three major drug-related materials in bile and urine were separated by HPLC and designated in order of reversed-phase elution as metabolites A, B, and C. The least polar metabolite (C) was shown by HPLC/particle beam/MS and HPLC/electrospray/MS to be the triester, U-94532. Metabolite C cochromatographed with a synthesized standard of U-94532A. Metabolite B was the glucuronide conjugate of the 5-hydroxy pyrimidinone, U-97294. Metabolite A was a product of glutathione addition to a putative pyrimidinone 4,5-epoxide. Mechanisms for the formation of metabolites A, B, and C based on metabolite structure and stability were proposed.