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Research ArticleArticle

INHIBITION OF MURINE CYTOCHROME P4501A BY TACRINE: IN VITRO STUDIES

Joanna Z. Peng, Rory P. Remmel and Ronald J. Sawchuk
Drug Metabolism and Disposition August 2004, 32 (8) 805-812; DOI: https://doi.org/10.1124/dmd.32.8.805
Joanna Z. Peng
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Ronald J. Sawchuk
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Abstract

Tacrine, a cholinesterase inhibitor, was approved for the treatment of Alzheimer's disease. Oxidative metabolism of tacrine occurs by CYP1A-catalyzed hydroxylation. In rats, it was observed that the area under the curve (AUC) of the second oral dose was consistently higher than the AUC after the first oral dose, which was not due to the accumulation of the drug in the plasma from the first dose. This finding suggested inhibition of the enzyme during metabolism or inhibition by a metabolite. The inhibitory mechanism was studied in liver and intestinal microsomes prepared from 3-methylcholanthrene-treated rats and with recombinant CYP1A1 and CYP1A2. Preincubation of CYP1A2 with tacrine and NADPH revealed a time-dependent inhibition of 7-ethoxyresorufin O-de-ethylation with a Ki of 1.94 μM and a kinact of 0.091 min-1. No time-dependent inhibition was observed with CYP1A1 or with 1-hydroxytacrine or 2-hydroxytacrine. Tacrine metabolism catalyzed by CYP1A was also carried out, and the partition ratio was estimated to be 22. A modified Michaelis-Menten equation involving mechanism-based inhibition was derived and used to analyze the data. Reasonable parameter fits were obtained indicating that this equation is suitable to describe metabolism data when the substrate is a mechanism-based inhibitor of the enzyme. The probable inactivation mechanism involves either hydrogen atom abstraction to produce a carbon-centered radical intermediate at the benzylic position or insertion of OH+ into a C-H bond with subsequent loss of water to produce a carbocation. Rapid rearrangement of the carbocation or radical and subsequent covalent binding of the tacrine moiety would result in enzyme inactivation.

Footnotes

  • The work described in this article was carried out in partial fulfillment of the requirements for a Ph.D. at the University of Minnesota (J.Z.P).

  • ABBREVIATIONS: P450, cytochrome P450; AUC, area under the curve; EROD, 7-ethoxyresorufin O-deethylation; 3-MC, 3-methylcholanthrene; THA, 1,2,3,4-tetrahydro-9-acridinamine (tacrine); HT, hydroxytacrine; ER, ethoxyresorufin; HPLC, high-performance liquid chromatography; PMSF, phenylmethylsulfonyl fluoride; RIM-cont, uninduced rat intestinal microsomes; RLM-MC, methylcholanthrene-induced rat liver microsomes; GSH, glutathione.

  • ↵1 Current address: Abbott Laboratories, Clinical Pharmacokinetics (Dept. R4PK, Bldg. AP13A), 100 Abbott Park Road, Abbott Park, IL 60064-6104.

    • Received January 7, 2004.
    • Accepted April 23, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 32 (8)
Drug Metabolism and Disposition
Vol. 32, Issue 8
1 Aug 2004
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Research ArticleArticle

INHIBITION OF MURINE CYTOCHROME P4501A BY TACRINE: IN VITRO STUDIES

Joanna Z. Peng, Rory P. Remmel and Ronald J. Sawchuk
Drug Metabolism and Disposition August 1, 2004, 32 (8) 805-812; DOI: https://doi.org/10.1124/dmd.32.8.805

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Research ArticleArticle

INHIBITION OF MURINE CYTOCHROME P4501A BY TACRINE: IN VITRO STUDIES

Joanna Z. Peng, Rory P. Remmel and Ronald J. Sawchuk
Drug Metabolism and Disposition August 1, 2004, 32 (8) 805-812; DOI: https://doi.org/10.1124/dmd.32.8.805
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