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Research ArticleArticle

THE EFFECT OF CIMETIDINE ON DEXTROMETHORPHAN O-DEMETHYLASE ACTIVITY OF HUMAN LIVER MICROSOMES AND RECOMBINANT CYP2D6

Maria Madeira, Marc Levine, Thomas K. H. Chang, Ahmad Mirfazaelian and Gail D. Bellward
Drug Metabolism and Disposition April 2004, 32 (4) 460-467; DOI: https://doi.org/10.1124/dmd.32.4.460
Maria Madeira
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Marc Levine
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Thomas K. H. Chang
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Ahmad Mirfazaelian
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Gail D. Bellward
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Abstract

Clinically, cimetidine therapy impairs the clearance of various drugs metabolized by CYP2D6, such as desipramine and sparteine. Cimetidine is known to reversibly inhibit CYP2D6 in vitro; however, Ki values are greater than plasma concentrations observed in vivo. There is evidence suggesting that this drug may act as an inactivator of cytochrome P450 (P450) enzymes after metabolic activation. Therefore, the purpose of this study was to determine whether cimetidine acts as a mechanism-based inactivator of CYP2D6. Dextromethorphan O-demethylation was used as a probe of CYP2D6 activity. The Vmax and Km of this reaction were 0.82 ± 0.06 nmol/min/nmol of P450 and 4.1 ± 0.1 μM, respectively, in pooled human liver microsomes; and 15.9 ± 0.8 nmol/min/nmol P450 and 1.4 ± 0.6 μM, respectively, with recombinant CYP2D6. With human liver microsomes, cimetidine competitively inhibited CYP2D6 (Ki = 38 ± 5 μM) and was a mixed inhibitor of recombinant CYP2D6 (Ki = 103 ± 17 μM). Preincubation of human liver microsomes with cimetidine and NADPH did not increase the inhibitory potency of cimetidine; however, preincubation with recombinant CYP2D6 resulted in enzyme inactivation that could be attenuated by the CYP2D6 inhibitor quinidine. The KI and kinact were estimated to be 77 μM and 0.03 min-1, respectively, and the half-life of inactivation was 25 min. Therefore, cimetidine may represent a class of compounds capable of inactivating specific cytochromes P450 in vivo, but for which conditions may not be achievable in vitro using human liver microsomes.

Footnotes

  • ↵1 Abbreviations used are: P450, cytochrome P450; ABT, 1-aminobenzotriazole; CAT, catalase; DEX, dextromethorphan; HPLC, high-performance liquid chromatography; SOD, superoxide dismutase.

  • This research was supported by the Canadian Institutes of Health Research (CIHR) Grant MOP-37974 to G.D.B. M.M. received a University Graduate Fellowship from the University of British Columbia and a Merck Research Laboratory Traineeship in Drug Metabolism and Pharmacokinetics. T.K.H.C. received a Research Career Award in the Health Sciences from CIHR and the Rx&D Health Research Foundation.

    • Received June 30, 2003.
    • Accepted December 29, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 32 (4)
Drug Metabolism and Disposition
Vol. 32, Issue 4
1 Apr 2004
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Research ArticleArticle

THE EFFECT OF CIMETIDINE ON DEXTROMETHORPHAN O-DEMETHYLASE ACTIVITY OF HUMAN LIVER MICROSOMES AND RECOMBINANT CYP2D6

Maria Madeira, Marc Levine, Thomas K. H. Chang, Ahmad Mirfazaelian and Gail D. Bellward
Drug Metabolism and Disposition April 1, 2004, 32 (4) 460-467; DOI: https://doi.org/10.1124/dmd.32.4.460

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Research ArticleArticle

THE EFFECT OF CIMETIDINE ON DEXTROMETHORPHAN O-DEMETHYLASE ACTIVITY OF HUMAN LIVER MICROSOMES AND RECOMBINANT CYP2D6

Maria Madeira, Marc Levine, Thomas K. H. Chang, Ahmad Mirfazaelian and Gail D. Bellward
Drug Metabolism and Disposition April 1, 2004, 32 (4) 460-467; DOI: https://doi.org/10.1124/dmd.32.4.460
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