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Research ArticleArticle

Cocaethylene Metabolism and Interaction with Cocaine and Ethanol: Role of Carboxylesterases

S. Casey Laizure, Timothy Mandrell, Naomi M. Gades and Robert B. Parker
Drug Metabolism and Disposition January 2003, 31 (1) 16-20; DOI: https://doi.org/10.1124/dmd.31.1.16
S. Casey Laizure
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Timothy Mandrell
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Naomi M. Gades
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Robert B. Parker
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Abstract

Carboxylesterases are important in the metabolism of cocaine, catalyzing the hydrolysis of cocaine to its two major metabolites, benzoylecgonine and ecgonine methyl ester. In the presence of ethanol, some cocaine undergoes transesterification with ethanol instead of hydrolysis with water producing the active metabolite, cocaethylene. The metabolic fate of cocaethylene is unknown, but given its structural similarity to cocaine, it was hypothesized that cocaethylene would also be metabolized by carboxylesterases and its elimination decreased in the presence of ethanol, as is cocaine's. Dogs were given cocaine alone, cocaethylene alone, cocaine and ethanol, cocaethylene and ethanol, and cocaine and cocaethylene on separate study days and sequential blood samples drawn. Plasma concentrations of cocaine, benzoylecgonine, and cocaethylene were determined by high-performance liquid chromatography. The pharmacokinetic dispositions of cocaine and cocaethylene were similar with clearance values of 0.91 ± 0.22 and 0.79 ± 0.16 l/min, and volumes of distribution of 2.6 ± 0.82 and 2.7 ± 0.47 l/kg, respectively. Both cocaine and cocaethylene clearances were decreased about 20% when given with ethanol. Following administration of cocaethylene alone, benzoylecgonine achieved similar plasma concentrations as those attained following cocaine alone, which indicates that benzoylecgonine is a major metabolite of cocaethylene. Carboxylesterases play an important role in the elimination of both cocaine and cocaethylene.

Footnotes

  • This study was supported by a grant from the National Heart, Lung, and Blood Institute, Grant R15-HL54311.

  • Abbreviations used are::
    hCE
    human carboxylesterase
    Cl
    clearance
    Vss
    steady state
    λz
    terminal elimination rate constant
    AUC
    area under the curve
    BE
    benzoylecgonine
    • Received June 10, 2002.
    • Accepted September 19, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 31 (1)
Drug Metabolism and Disposition
Vol. 31, Issue 1
1 Jan 2003
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Research ArticleArticle

Cocaethylene Metabolism and Interaction with Cocaine and Ethanol: Role of Carboxylesterases

S. Casey Laizure, Timothy Mandrell, Naomi M. Gades and Robert B. Parker
Drug Metabolism and Disposition January 1, 2003, 31 (1) 16-20; DOI: https://doi.org/10.1124/dmd.31.1.16

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Research ArticleArticle

Cocaethylene Metabolism and Interaction with Cocaine and Ethanol: Role of Carboxylesterases

S. Casey Laizure, Timothy Mandrell, Naomi M. Gades and Robert B. Parker
Drug Metabolism and Disposition January 1, 2003, 31 (1) 16-20; DOI: https://doi.org/10.1124/dmd.31.1.16
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