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Research ArticleArticle

Binding and Hydrolysis of Meperidine by Human Liver Carboxylesterase hCE-1

Jing Zhang, Joe C. Burnell, Natividad Dumaual and William F. Bosron
Journal of Pharmacology and Experimental Therapeutics July 1999, 290 (1) 314-318;
Jing Zhang
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Joe C. Burnell
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Natividad Dumaual
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William F. Bosron
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Abstract

Human liver carboxylesterases catalyze the hydrolysis of apolar drug or xenobiotic esters into more soluble acid and alcohol products for elimination. Two carboxylesterases, hCE-1 and hCE-2, have been purified and characterized with respect to their role in cocaine and heroin hydrolysis. The binding of meperidine (Demerol) and propoxyphene (Darvon) was examined in a competitive binding, spectrophotometric assay. The hCE-1 and hCE-2 bound both drugs, withKi values in the 0.4- to 1.3-mM range. Meperidine was hydrolyzed to meperidinic acid and ethanol by hCE-1 but not hCE-2. The Km of hCE-1 for meperidine was 1.9 mM and the kcat(catalytic rate constant) was 0.67 min−1. Hydrolysis of meperidine by hCE-1 was consistent with its specificity for hydrolysis of esters containing simple aliphatic alcohol substituents. Hence, hCE-1 in human liver microsomes may play an important role in meperidine elimination. Propoxyphene was not hydrolyzed by hCE-1 or hCE-2. This observation is consistent with the absence of a major hydrolytic pathway for propoxyphene metabolism in humans.

Footnotes

  • Send reprint requests to: William F. Bosron, Ph.D., 405 Medical Sciences, Indiana University School of Medicine, Indianapolis, IN 46202-5122. E-mail:wbosron{at}iupui.edu

  • ↵1 The study was supported by Grant R01-DA-06836 from the National Institute on Drug Abuse.

  • Abbreviations:
    hCE-1 and hCE-2
    human liver carboxylesterases 1 and 2
    GC-MS
    gas chromatography mass spectroscopy
    Ki
    inhibition constant
    Km
    Michaelis constant
    kcat
    catalytic rate constant
    • Received September 1, 1998.
    • Accepted February 18, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 290 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 290, Issue 1
1 Jul 1999
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Research ArticleArticle

Binding and Hydrolysis of Meperidine by Human Liver Carboxylesterase hCE-1

Jing Zhang, Joe C. Burnell, Natividad Dumaual and William F. Bosron
Journal of Pharmacology and Experimental Therapeutics July 1, 1999, 290 (1) 314-318;

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Research ArticleArticle

Binding and Hydrolysis of Meperidine by Human Liver Carboxylesterase hCE-1

Jing Zhang, Joe C. Burnell, Natividad Dumaual and William F. Bosron
Journal of Pharmacology and Experimental Therapeutics July 1, 1999, 290 (1) 314-318;
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