Vol. 26, Issue 10, 993-1000, October 1998

Metabolism of -Phosphonosulfonate Squalene Synthase Inhibitors
I. Disposition of a Farnesylethyl -Phosphonosulfonate and Ester Prodrugs in Rats

Shih-Jung Lan, Dolly C. Hsieh, John W. Hillyer, R. Marcus Fancher, Kent J. Rinehart, Bethanne M. Warrack, and Ronald E. White

Departments of Metabolism and Pharmacokinetics (S.-J.L., D.C.H., J.W.H., R.M.F., K.J.R., R.E.W.) and Analytical Research and Development (B.M.W.), Bristol-Myers Squibb Pharmaceutical Research Institute

The disposition of I [(E,E)-6,10,14-trimethyl-1-phosphono-5,9,13-pentadecatriene-1-sulfonic acid] and its mono- (II), di- (III), and triester (IV) prodrugs in rats was studied with ¹⁴C-labeled compounds. After iv administration of I (15 µmol/kg), radioactivity in plasma was measurable up to 96 hr and averaged 0.026 µg-eq/ml. I accounted for >50% of the radioactivity in plasma and had an apparent half-life of 4 hr. After oral administration of the same dose, the maximal plasma concentration of radioactivity averaged 0.108 µg-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 accumulation of radioactivity in bone was observed. I (3%) and II (6%) were poorly 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 radioactivity in urine and ~50% of the radioactivity in bile for each compound. Metabolism appeared to occur primarily at the farnesyl moiety, presumably by the same pathways as for farnesyl-1-pyrophosphate.