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Research ArticleArticle

Simultaneous Pharmacokinetic Modeling of Cocaine and Its Metabolites, Norcocaine and Benzoylecgonine, after Intravenous and Oral Administration in Rats

Lei Sun and Chyan E. Lau
Drug Metabolism and Disposition September 2001, 29 (9) 1183-1189;
Lei Sun
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Chyan E. Lau
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Abstract

To accurately assess the mechanism of involvement of the active metabolite norcocaine in the effects of oral cocaine, it is essential to determine the rate and extent of the formation of norcocaine. Although this study was designed specifically for this aim, it was also of interest to characterize the metabolite kinetics of benzoylecgonine for comparative purpose. We first characterized the pharmacokinetics of cocaine, norcocaine, and benzoylecgonine by the i.v. route of administration; all three drugs decayed biexponentially. These pharmacokinetic estimates were then used for determination of the formation of norcocaine and benzoylecgonine after i.v. and p.o. (20–40 mg/kg) cocaine administration. Althought1/2α, andt1/2β were similar across the three compounds, the values of volume of distribution in the central compartment and clearance for benzoylecgonine were much smaller than those of cocaine and norcocaine. Norcocaine was not detected following i.v. cocaine; however, serum norcocaine concentrations were as high as those of oral cocaine. Both routes of cocaine administration produced benzoylecgonine. A pharmacokinetic model for the metabolite kinetics was proposed by sequentially adding the models that most adequately described the formation of each metabolite to the model of cocaine. For oral cocaine, the absolute bioavailability was 3.48%, whereas 6.04 and 2.26% of cocaine were converted to benzoylecgonine and norcocaine, respectively, during first-pass absorption regardless of dose. Furthermore, the majority of norcocaine and 92% of benzoylecgonine were formed during the first-pass absorption, leaving 8% of benzoylecgonine produced in systemic circulation. The profile of norcocaine as a metabolite confirmed the involvement of norcocaine in cocaine's behavioral effects.

Footnotes

  • This research was supported by Grants R01 DA05305 and R01 DA12975 from the National Institute on Drug Abuse.

  • Abbreviations used are::
    PD
    pharmacodynamics
    PK
    pharmacokinetics
    AIC
    Akaike's information criterion
    Vc
    volume of distribution in the central compartment
    CL
    clearance
    Vss
    volume of distribution at steady state
    MRT
    mean residence time
    AUC
    area under the curve
    COC
    cocaine
    NORC
    norcocaine
    BE
    benzoylecgonine
    • Received February 12, 2001.
    • Accepted May 9, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 29 (9)
Drug Metabolism and Disposition
Vol. 29, Issue 9
1 Sep 2001
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Research ArticleArticle

Simultaneous Pharmacokinetic Modeling of Cocaine and Its Metabolites, Norcocaine and Benzoylecgonine, after Intravenous and Oral Administration in Rats

Lei Sun and Chyan E. Lau
Drug Metabolism and Disposition September 1, 2001, 29 (9) 1183-1189;

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Research ArticleArticle

Simultaneous Pharmacokinetic Modeling of Cocaine and Its Metabolites, Norcocaine and Benzoylecgonine, after Intravenous and Oral Administration in Rats

Lei Sun and Chyan E. Lau
Drug Metabolism and Disposition September 1, 2001, 29 (9) 1183-1189;
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