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Research ArticleArticle

Cytochrome P450 3A4-Mediated Interaction of Diclofenac and Quinidine

Jason S. Ngui, Wei Tang, Ralph A. Stearns, Magang Shou, Randall R. Miller, Yong Zhang, Jiunn H. Lin and Thomas A. Baillie
Drug Metabolism and Disposition September 2000, 28 (9) 1043-1050;
Jason S. Ngui
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Wei Tang
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Ralph A. Stearns
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Magang Shou
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Randall R. Miller
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Yong Zhang
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Jiunn H. Lin
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Thomas A. Baillie
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Abstract

The metabolism of diclofenac to its 5-hydroxylated derivative in humans is catalyzed by cytochrome P450 (CYP)3A4. We report herein that in vitro this biotransformation pathway is stimulated by quinidine. When diclofenac was incubated with human liver microsomes in the presence of quinidine, the formation of 5-hydroxydiclofenac increased ∼6-fold relative to controls. Similar phenomena were observed with diastereoisomers of quinidine, including quinine and thethreo epimers, which produced an enhancement in the formation of 5-hydroxydiclofenac in the order of 6- to 9-fold. This stimulation of diclofenac metabolism was diminished when human liver microsomes were pretreated with a monoclonal inhibitory antibody against CYP3A4. In contrast, neither cytochromeb5 nor CYP oxidoreductase appeared to mediate the stimulation of diclofenac metabolism by quinidine, suggesting that the effect of quinidine is mediated through CYP3A4 protein. Further kinetic analyses indicated thatVmax values for the conversion of diclofenac to its 5-hydroxy derivative increased 4.5-fold from 13.2 to 57.6 nmol/min/nmol of CYP with little change inKm (71–56 μM) over a quinidine concentration range of 0 to 30 μM. Conversely, the metabolism of quinidine was not affected by the presence of diclofenac; theKm value estimated for the formation of 3-hydroxyquinidine was ∼1.5 μM, similar to the quinidine concentration required to produce 50% of the maximum stimulatory effect on diclofenac metabolism. It appears that the enhancement of diclofenac metabolism does not interfere with quinidine's access to the ferriheme-oxygen complex, implicating the presence of both compounds in the active site of CYP3A4 at the same time. Finally, a ∼4-fold increase in 5-hydroxydiclofenac formation was observed in human hepatocyte suspensions containing diclofenac and quinidine, demonstrating that this type of drug-drug interaction occurs in intact cells.

Footnotes

  • Send reprint requests to: Wei Tang, Ph.D., Department of Drug Metabolism, Merck & Co., PO Box 2000, RY800-B211, Rahway, NJ 07065. E-mail: wei_tang{at}merck.com

  • Abbreviations used are::
    CYP
    cytochrome P450
    LC/MS/MS
    liquid chromatography-tandem mass spectrometry
    OR
    NADPH-cytochrome P450 oxidoreductase
    • Received April 3, 2000.
    • Accepted June 1, 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

Cytochrome P450 3A4-Mediated Interaction of Diclofenac and Quinidine

Jason S. Ngui, Wei Tang, Ralph A. Stearns, Magang Shou, Randall R. Miller, Yong Zhang, Jiunn H. Lin and Thomas A. Baillie
Drug Metabolism and Disposition September 1, 2000, 28 (9) 1043-1050;

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Research ArticleArticle

Cytochrome P450 3A4-Mediated Interaction of Diclofenac and Quinidine

Jason S. Ngui, Wei Tang, Ralph A. Stearns, Magang Shou, Randall R. Miller, Yong Zhang, Jiunn H. Lin and Thomas A. Baillie
Drug Metabolism and Disposition September 1, 2000, 28 (9) 1043-1050;
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