METABOLISM OF ALPHA-PHOSPHONOSULFONATE SQUALENE SYNTHASE INHIBITORS -I - DISPOSITION OF A FARNESYLETHYL ALPHA-PHOSPHONOSULFONATE AND ESTERPRODRUGS IN RATS

The disposition of I thyl-1-phosphono-5,9,13-pentadecatriene-1-sulfoni c acid] and its mono- (II), di- (III), and triester (IV) prodrugs in r ats was studied with C-14-labeled compounds. After iv administration o f I (15 mu mol/kg), radioactivity in plasma was measurable up to 96 hr and averaged 0.026 mu g-eq/ml. I accounted for >50% of the radioactiv ity in plasma and had an apparent half-life of 4 hr. After oral admini stration of the same dose, the maximal plasma concentration of radioac tivity averaged 0.108 mu g-eq/ml at 6 hr. In 96 hr, 19 and 73% of the iv dose and 2 and 97% of the po dose was excreted in urine and feces, respectively. The absorption was 2.4%, based on the plasma data. In 12 hr after an iv dose of I to bile duct-cannulated rats, 41 and 14% of the dose was excreted in bile and urine, respectively. I accounted for 51% of the radioactivity in bile and a negligible amount in urine. At 12 hr after iv dosing, liver retained 31% of the dose. No accumulatio n of radioactivity in bone was observed. I (3%) and II (6%) were poorl y absorbed. Enhanced absorption was observed for III (80%) and IV (45% ). No I or metabolites of I were found in bile or urine of rats dosed with the prodrugs. The structures of two metabolites each for I, III, and IV were proposed. Together, they accounted for >80% of the radioac tivity in urine and similar to 50% of the radioactivity in bile for ea ch compound. Metabolism appeared to occur primarily at the farnesyl mo iety, presumably by the same pathways as for farnesyl-1-pyrophosphate.