Abstract
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.
Footnotes
- Abbreviations used are::
- compound I
- (1-(3-chlorophenyl)-4-[(1-(4-cyanobenzyl)-[1H]-imidazol-5-yl)methyl]piperazin-2-one)
- FPTase
- farnesyl-protein transferase
- HPLC
- high-pressure liquid chromatography
- AUC
- area under plasma concentration-time curve
- Vdss
- volume of distribution
- CL
- clearance
- LC-MS/MS
- liquid chromatography-tandem mass spectrometry
- CAD
- collisionally activated dissociation
- NOE
- nuclear Overhauser effect
- Received May 23, 2001.
- Accepted September 14, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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