METABOLISM OF A BISPHOSPHONATE ESTER (PNU-91638) IN RAT

1. Metabolites of the cyclic bisphosphonate ester, '-bis-(5,5-dimethyl -1,3,2-dioxaphosphorinan-2-yl)] butanoyl-3-fluoro-benzene (PNU-91638) in bile or urine of the male Sprague-Dawley rat were characterized by mass spectrometry. The chronically bile duct/duodenal-cannulated male rats received a single oral dose cf 100 mg/kg [C-13] [C-14]PNU-91638. Bile and urine samples were analysed for radioactivity and profiled by hplc with radiometric and UV detection. 2. The 0-28-h bile and urine accounted for 46.0 and 19.7 % of dose respectively. The structures of radioactive peaks were investigated by ionspray and liquid secondary i on mass spectrometry (LSIMS) and LSIMS/MS analysis. 3. Major metabolit es in urine included two regioisomeric phenol glucuronides, a gem-meth yl hydroxylated metabolite of the bisphosphorate heterocycle, a phenol metabolite, parent drug and a benzylic alcohol metabolite. Additional metabolites in bile included an unstable phenol/glutathione adduct (f rom a putative epoxide intermediate) with several minor isobaric regio isomers, and a carboxylic acid derived from the gem methyl hydroxylate d bisphosphonate ring. 4. The structures proposed have not been confir med by nmr due to discontinuation of the development of PNU-91638.