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Research ArticleArticle

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
Drug Metabolism and Disposition December 2001, 29 (12) 1578-1587;
Rominder Singh
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I-Wu Chen
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Lixia Jin
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Maria V. Silva
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Byron H. Arison
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Jiunn H. Lin
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Bradley K. Wong
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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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Drug Metabolism and Disposition: 29 (12)
Drug Metabolism and Disposition
Vol. 29, Issue 12
1 Dec 2001
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Research ArticleArticle

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
Drug Metabolism and Disposition December 1, 2001, 29 (12) 1578-1587;

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Research ArticleArticle

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
Drug Metabolism and Disposition December 1, 2001, 29 (12) 1578-1587;
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