RT Journal Article SR Electronic T1 Metabolism of the bisphosphonate ester U-91502 in rats. JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 65 OP 73 VO 24 IS 1 A1 J G Slatter A1 K L Feenstra A1 M J Hauer A1 D A Kloosterman A1 A H Parton A1 P E Sanders A1 G Scott A1 W Speed YR 1996 UL http://dmd.aspetjournals.org/content/24/1/65.abstract AB 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.