RT Journal Article SR Electronic T1 Pharmacokinetics and Metabolism of a Ras Farnesyl Transferase Inhibitor in Rats and Dogs: In Vitro-In Vivo Correlation JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 1578 OP 1587 VO 29 IS 12 A1 Rominder Singh A1 I-Wu Chen A1 Lixia Jin A1 Maria V. Silva A1 Byron H. Arison A1 Jiunn H. Lin A1 Bradley K. Wong YR 2001 UL http://dmd.aspetjournals.org/content/29/12/1578.abstract AB 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 terminalt1/2 of 41 min. The plasma clearance (CLp) and volume of distribution (Vdss) 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. The American Society for Pharmacology and Experimental Therapeutics