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Research ArticleArticle

Metabolism of Ezlopitant, a Nonpeptidic Substance P Receptor Antagonist, in Liver Microsomes: Enzyme Kinetics, Cytochrome P450 Isoform Identity, and In Vitro-In Vivo Correlation

R. Scott Obach
Drug Metabolism and Disposition September 2000, 28 (9) 1069-1076;
R. Scott Obach
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Abstract

The enzyme kinetics of the metabolism of ezlopitant in liver microsomes from various species have been determined. The rank order of the species with regard to the in vitro intrinsic clearance of ezlopitant was monkey ≫ guinea pig > rat ≫ dog > human. CJ-12,764, a benzyl alcohol analog, was observed as a major metabolite, and a dehydrogenated metabolite (CJ-12,458) was equally important in human liver microsomes. Scale-up of the liver microsomal intrinsic clearance data and correcting for both serum protein binding and nonspecific microsomal binding yielded predicted hepatic clearance values that showed a good correlation with in vivo systemic blood clearance values. Including microsomal binding was necessary to achieve agreement between hepatic clearance values predicted from in vitro data and systemic clearance values measured in vivo. Cytochrome P450 (CYP) 3A4, 3A5, and 2D6 demonstrated the ability to metabolize ezlopitant to CJ-12,458 and CJ-12,764. However, in liver microsomes, the CYP3A isoforms appear to play a substantially more important role in the metabolism of ezlopitant than CYP2D6, as assessed through the use of CYP-specific inhibitors, correlation to isoform-specific marker substrate activities, and appropriate scale-up of enzyme kinetic data generated in microsomes containing individual heterologously expressed recombinant CYP isoforms. The apparent predominance of CYP3A over CYP2D6 is consistent with observations of the pharmacokinetics of ezlopitant in humans in vivo.

Footnotes

  • Send reprint requests to: Dr. R. Scott Obach, Drug Metabolism Department, Central Research, Pfizer, Inc., Groton, CT, 06340. E-mail: ronald_s_obach{at}groton.pfizer.com

  • Abbreviations used are::
    CYP
    cytochrome 450
    TAO
    triacetyloleandomycin
    TEA
    triethylamine
    KMapp
    Michaelis constant
    CL′int
    intrinsic clearance
    fu
    unbound fraction
    MS
    mass spectrometry
    • Received March 29, 2000.
    • Accepted May 22, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 28 (9)
Drug Metabolism and Disposition
Vol. 28, Issue 9
1 Sep 2000
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Research ArticleArticle

Metabolism of Ezlopitant, a Nonpeptidic Substance P Receptor Antagonist, in Liver Microsomes: Enzyme Kinetics, Cytochrome P450 Isoform Identity, and In Vitro-In Vivo Correlation

R. Scott Obach
Drug Metabolism and Disposition September 1, 2000, 28 (9) 1069-1076;

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Research ArticleArticle

Metabolism of Ezlopitant, a Nonpeptidic Substance P Receptor Antagonist, in Liver Microsomes: Enzyme Kinetics, Cytochrome P450 Isoform Identity, and In Vitro-In Vivo Correlation

R. Scott Obach
Drug Metabolism and Disposition September 1, 2000, 28 (9) 1069-1076;
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