Vol. 29, Issue 12, 1578-1587, December 2001

Pharmacokinetics and Metabolism of a Ras Farnesyl Transferase Inhibitor in Rats and Dogs: In Vitro-In Vivo Correlation

Rominder Singh, I-Wu Chen, Lixia Jin, Maria V. Silva, Byron H. Arison, Jiunn H. Lin, and Bradley K. Wong

Department of Drug Metabolism, Merck Research Labs, West Point, Pennsylvania (R.S., B.K.W., I-W.C, L.J., J.H.L.); and Department of Drug Metabolism, Merck Research Labs, Rahway, New Jersey (M.V.S., B.H.A.)

Compound I (1-(3-chlorophenyl)-4-[(1-(4-cyanobenzyl)-1H-imidazol-5-yl)methyl]piperazin-2-one) is a potent and selective inhibitor of farnesyl-protein transferase (FPTase). The pharmacokinetics and metabolism of compound I displayed species differences in rats and dogs. After oral administration, the drug was well absorbed in dogs but less so in rats. Following i.v. administration, compound I was cleared rapidly in rats in a polyphasic manner with a terminal t_1/2 of 41 min. The plasma clearance (CL_p) and volume of distribution (V_dss) were 41.2 ml/min/kg and 1.2 l/kg, respectively. About 1% of the dose was excreted in rat bile and urine as unchanged drug over a period of 24 h, suggesting that biotransformation is the major route of elimination of compound I. Using liquid chromatography (LC)-tandem mass spectometry, nineteen metabolites of compound I were identified in urine and bile from dogs and rats. Structures of two major metabolites were confirmed by LC-NMR. N-Dealkylation and phase II metabolism were the major metabolic pathways. Animal and human liver microsomal intrinsic clearance values were scaled to predict hepatic clearance and half-life in humans, and the predicted values were in good agreement to the in vivo data.