PT  - JOURNAL ARTICLE
AU  - Singh, Rominder
AU  - Chen, I-Wu
AU  - Jin, Lixia
AU  - Silva, Maria V.
AU  - Arison, Byron H.
AU  - Lin, Jiunn H.
AU  - Wong, Bradley K.
TI  - Pharmacokinetics and Metabolism of a <em>Ras</em> Farnesyl Transferase Inhibitor in Rats and Dogs: In Vitro-In Vivo Correlation
DP  - 2001 Dec 01
TA  - Drug Metabolism and Disposition
PG  - 1578--1587
VI  - 29
IP  - 12
4099  - http://dmd.aspetjournals.org/content/29/12/1578.short
4100  - http://dmd.aspetjournals.org/content/29/12/1578.full
SO  - Drug Metab Dispos2001 Dec 01; 29
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