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Drug Metabolism & Disposition

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Research ArticleArticle

An In Vitro Model for Predicting In Vivo Inhibition of Cytochrome P450 3A4 by Metabolic Intermediate Complex Formation

Bradley S. Mayhew, David R. Jones and Stephen D. Hall
Drug Metabolism and Disposition September 2000, 28 (9) 1031-1037;
Bradley S. Mayhew
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David R. Jones
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Stephen D. Hall
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Abstract

An in vitro model is proposed to account for the clinically observed inhibition of cytochrome P450 (CYP) 3A that results from administration of clarithromycin, fluoxetine, or diltiazem. Rates for loss of CYP3A4 enzymatic activity resulting from metabolic intermediate complex formation and the concentration dependencies thereof were determined in vitro for clarithromycin, fluoxetine, andN-desmethyl diltiazem, which is the primary metabolite of diltiazem. Using the in vitro concentration-dependent rates for loss of activity, in vivo rates of CYP3A4 inactivation were predicted for these compounds at a clinically relevant unbound plasma concentration of 0.1 μM. Based on the predicted rates combined with published rates for in vivo CYP3A degradation, our model predicts that fluoxetine, clarithromycin, and the primary metabolite of diltiazem reduce the steady-state concentration of liver CYP3A4 to approximately 72, 39, or 21% of initial levels, respectively. These reductions correspond to 1.4-, 2.6-, or 4.7-fold increases, respectively, in the area under the plasma concentration-time curve of a coadministered drug that is eliminated exclusively by hepatic CYP3A4 metabolism. These predicted results are in good agreement with reported clinical data. The major implication of this work is that fluoxetine, clarithromycin, and the primary metabolite of diltiazem, at clinically relevant concentrations, inactivate CYP3A4 enzymatic activity at rates sufficient to affect in vivo concentrations of CYP3A4 and thereby affect the clearance of compounds eliminated by this pathway. We speculate that mechanisms involving substrate-mediated mechanistic inactivation of CYPs play a major role in many clinically observed drug-drug interactions.

Footnotes

  • Send reprint requests to: Stephen D. Hall, Ph.D., Indiana University School of Medicine, Division of Clinical Pharmacology, Wishard Memorial Hospital, OPW 320, 1001 West 10th St., Indianapolis, IN 46202. E-mail: sdhall{at}iupui.edu

  • This work was supported by Public Health Service Grant AG13718.

  • Abbreviations used are::
    CYP
    cytochrome P450
    AUC
    area under the plasma concentration-time curve
    b5
    cytochromeb5
    Clint
    intrinsic clearance
    kdegrad
    rate constant for endogenous enzyme degradation
    kinact
    rate constant for mechanistic inactivation
    ksynth
    rate constant for endogenous enzyme synthesis
    Ki
    dissociation constant for reversible inhibition
    KI
    inactivator concentration that supports half the maximal rate of mechanistic inactivation
    λ
    apparent rate constant for enzyme degradation
    MA
    N-desmethyl diltiazem
    MIC
    metabolic intermediate complex
    GC
    gas chromatography
    MS
    mass spectroscopy
    • Received December 2, 1999.
    • Accepted May 22, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 28 (9)
Drug Metabolism and Disposition
Vol. 28, Issue 9
1 Sep 2000
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Research ArticleArticle

An In Vitro Model for Predicting In Vivo Inhibition of Cytochrome P450 3A4 by Metabolic Intermediate Complex Formation

Bradley S. Mayhew, David R. Jones and Stephen D. Hall
Drug Metabolism and Disposition September 1, 2000, 28 (9) 1031-1037;

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Research ArticleArticle

An In Vitro Model for Predicting In Vivo Inhibition of Cytochrome P450 3A4 by Metabolic Intermediate Complex Formation

Bradley S. Mayhew, David R. Jones and Stephen D. Hall
Drug Metabolism and Disposition September 1, 2000, 28 (9) 1031-1037;
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