Pharmacokinetics and metabolism of a RAS farnesyl transferase inhibitor in rats and dogs: in vitro-in vivo correlation.
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.
Singh
R
R
Department of Drug Metabolism, Merck Research Labs, West Point, Pennsylvania 19486, USA. romi_singh@merck.com
Chen
I W
IW
Jin
L
L
Silva
M V
MV
Arison
B H
BH
Lin
J H
JH
Wong
B K
BK
D000465:Algorithms; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D019540:Area Under Curve; D001646:Bile / Q000378:metabolism; D001652:Bile Ducts / Q000378:metabolism; D001711:Biotransformation; D001798:Blood Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D006207:Half-Life; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D007408:Intestinal Absorption; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
C439809:1-(3-chlorophenyl)-4-(1-(4-cyanobenzyl)imidazolylmethyl)-2-piperazinone; D001798:Blood Proteins; D004791:Enzyme Inhibitors; D007093:Imidazoles; D010879:Piperazines; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase