METABOLISM OF THE BISPHOSPHONATE ESTER U-91502 IN RATS

The major metabolites of the bisphosphonate ester U-91502 were isolate d from the bile and urine of male Sprague-Dawley rats and identified b y NMR and MS. Bile duct-exteriorized and taurocholate-supplemented rat s received single oral doses of 10-140 mg/kg of labeled U-91502, Analy sis of radioactivity in bile, urine, and feces showed that U-91502-rel ated radioactivity was rapidly excreted, predominantly in bile, achiev ing peak concentrations in bile of 1250 +/- 622 mu g-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 reve rsed-phase elution as metabolites A, B, and C. The least polar metabol ite (C) was shown by HPLC/particle beam/MS and HPLC/electrospray/MS to be the triester, U-94532, Metabolite C cochromatographed with a synth esized standard of U-94532A, Metabolite B was the glucuronide conjugat e of the B-hydroxy pyrimidinone, U-97294, Metabolite A was a product o f glutathione addition to a putative pyrimidinone 4,5-epoxide, Mechani sms for the formation of metabolites A, B, and C based on metabolite s tructure and stability were proposed.