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Research ArticleArticle

METABOLISM OF ALFENTANIL BY CYTOCHROME P4503A (CYP3A) ENZYMES

Theresa Mariero Klees, Pamela Sheffels, Ola Dale and Evan D. Kharasch
Drug Metabolism and Disposition March 2005, 33 (3) 303-311; DOI: https://doi.org/10.1124/dmd.104.002709
Theresa Mariero Klees
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Pamela Sheffels
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Ola Dale
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Evan D. Kharasch
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Abstract

The synthetic opioid alfentanil is an analgesic and an in vivo probe for hepatic and first-pass CYP3A activity. Alfentanil is a particularly useful CYP3A probe because pupil diameter change is a surrogate for plasma concentrations, thereby affording noninvasive assessment of CYP3A. Alfentanil undergoes extensive CYP3A4 metabolism via two major pathways, forming noralfentanil and N-phenylpropionamide. This investigation evaluated alfentanil metabolism in vitro to noralfentanil and N-phenylpropionamide, by expressed CYP3A5 and CYP3A7 in addition to CYP3A4, with and without coexpressed or exogenous cytochrome b5. Effects of the CYP3A inhibitors troleandomycin and ketoconazole were also determined. Rates of noralfentanil and N-phenylpropionamide formation by CYP3A4 and 3A5 in the absence of b5 were generally equivalent, although the metabolite formation ratio differed, whereas those by CYP3A7 were substantially less. CYP3A4 and 3A5 were equipotently inhibited by troleandomycin, whereas ketoconazole was an order of magnitude more potent toward CYP3A4. Cytochrome b5 qualitatively and quantitatively altered alfentanil metabolism, with b5 coexpression having a greater effect than exogenous addition. Addition or coexpression of b5 markedly stimulated the formation of both metabolites and changed the formation of noralfentanil but not N-phenylpropionamide from apparent single-site to multisite Michaelis-Menten kinetics. These results demonstrate that alfentanil is a substrate for CYP3A5 in addition to CYP3A4, and the effects of the CYP3A inhibitors troleandomycin and ketoconazole are CYP3A enzyme-selective. Alfentanil is one of the few CYP3A substrates that is metabolized in vitro as avidly by both CYP3A4 and 3A5. Polymorphic CYP3A5 expression may contribute to inter-individual variability in alfentanil metabolism.

Footnotes

  • Supported by National Institutes of Health Grants R01-GM63674, R01-DA14211, and K24-DA00417. Presented in part at the annual meeting of the American Society of Anesthesiologists, Las Vegas, NV, October 23–27, 2004.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.104.002709.

  • ABBREVIATIONS: AMX, N-phenylpropionamide; P450, cytochrome P450; TAO, troleandomycin; LC-MS, liquid chromatography-mass spectrometry; b5, cytochrome b5.

    • Received October 19, 2004.
    • Accepted November 18, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 33 (3)
Drug Metabolism and Disposition
Vol. 33, Issue 3
1 Mar 2005
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Research ArticleArticle

METABOLISM OF ALFENTANIL BY CYTOCHROME P4503A (CYP3A) ENZYMES

Theresa Mariero Klees, Pamela Sheffels, Ola Dale and Evan D. Kharasch
Drug Metabolism and Disposition March 1, 2005, 33 (3) 303-311; DOI: https://doi.org/10.1124/dmd.104.002709

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Research ArticleArticle

METABOLISM OF ALFENTANIL BY CYTOCHROME P4503A (CYP3A) ENZYMES

Theresa Mariero Klees, Pamela Sheffels, Ola Dale and Evan D. Kharasch
Drug Metabolism and Disposition March 1, 2005, 33 (3) 303-311; DOI: https://doi.org/10.1124/dmd.104.002709
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