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Research ArticleArticle

Pharmacokinetics and Metabolism of a Cysteinyl Leukotriene-1 Receptor Antagonist from the Heterocyclic Chromanol Series in Rats: In Vitro-In Vivo Correlation, Gender-Related Differences, Isoform Identification, and Comparison with Metabolism in Human Hepatic Tissue

Alexander V. Kuperman, Amit S. Kalgutkar, Anthony Marfat, Robert J. Chambers and Theodore E. Liston
Drug Metabolism and Disposition November 2001, 29 (11) 1403-1409;
Alexander V. Kuperman
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Amit S. Kalgutkar
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Anthony Marfat
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Robert J. Chambers
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Theodore E. Liston
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Abstract

CP-199,331 is a potent antagonist of the cysteinyl leukotriene-1 (LT1) receptor, targeted for the treatment of asthma. The pharmacokinetic/metabolism properties of CP-199,331 were studied in rats and compared with those in human liver microsomes/hepatocytes. In vitro biotransformation of CP-199,331 in rat and human hepatocytes was similar, consisting primarily of CP-199,331O-demethylation. Marked sex-related differences in plasma clearance (CLp) of CP-199,331 were observed in rats: 51 and 1.2 ml/min/kg in males and females, respectively. This difference in CLp was attributed to gender differences in metabolizing capacity because Vmax andKm values for CP-199,331 metabolism were 30-fold higher and 8-fold lower, respectively, in male rat liver microsomes compared with female microsomes. Scale-up of the in vitro microsomal data predicted hepatic clearance (CLh) of 64 and 2.5 ml/min/kg in male and female rats, respectively. These values were in close agreement with the in vivo CLp, suggesting that CP-199,331 CLp in male and female rats was entirely due to hepatic metabolism. Studies with rat recombinant cytochromes P450 and anti-rat cytochrome P450 (CYP) antibodies revealed the involvement of male rat-specific CYP2C11 in the metabolism of CP-199,331. In contrast, CP-199,331 metabolism in human liver microsomes was principally mediated by CYP3A4. The projected human clearance in liver microsomes and hepatocytes varied 6-fold from low to moderate, depending on CYP3A4 activity. Considering thatO-demethylation is the major route of elimination in humans, the in vivo clearance of CP-199,331 may exhibit moderate variability, depending on CYP3A4 abundance in the human population.

Footnotes

  • Abbreviations used are::
    Cys-LT
    cysteinyl leukotriene
    CYP
    cytochrome P450
    CLp
    plasma clearance
    CLh
    hepatic clearance
    HPLC-UV
    high performance liquid chromatography-ultraviolet spectroscopy
    CL′int
    intrinsic clearance
    rCYP
    recombinant cytochrome P450
    LC/MS/MS
    liquid chromatography/mass spectrometry/mass spectrometry
    Rt
    retention time
    • Received May 9, 2001.
    • Accepted July 17, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 29 (11)
Drug Metabolism and Disposition
Vol. 29, Issue 11
1 Nov 2001
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Research ArticleArticle

Pharmacokinetics and Metabolism of a Cysteinyl Leukotriene-1 Receptor Antagonist from the Heterocyclic Chromanol Series in Rats: In Vitro-In Vivo Correlation, Gender-Related Differences, Isoform Identification, and Comparison with Metabolism in Human Hepatic Tissue

Alexander V. Kuperman, Amit S. Kalgutkar, Anthony Marfat, Robert J. Chambers and Theodore E. Liston
Drug Metabolism and Disposition November 1, 2001, 29 (11) 1403-1409;

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Research ArticleArticle

Pharmacokinetics and Metabolism of a Cysteinyl Leukotriene-1 Receptor Antagonist from the Heterocyclic Chromanol Series in Rats: In Vitro-In Vivo Correlation, Gender-Related Differences, Isoform Identification, and Comparison with Metabolism in Human Hepatic Tissue

Alexander V. Kuperman, Amit S. Kalgutkar, Anthony Marfat, Robert J. Chambers and Theodore E. Liston
Drug Metabolism and Disposition November 1, 2001, 29 (11) 1403-1409;
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