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Research ArticleArticle

Interaction of Diclofenac and Quinidine in Monkeys: Stimulation of Diclofenac Metabolism

Wei Tang, Ralph A. Stearns, Gloria Y. Kwei, Susan A. Iliff, Randall R. Miller, Marjorie A. Egan, Nathan X. Yu, Dennis C. Dean, Sanjeev Kumar, Magang Shou, Jiunn H. Lin and Thomas A. Baillie
Journal of Pharmacology and Experimental Therapeutics December 1999, 291 (3) 1068-1074;
Wei Tang
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Ralph A. Stearns
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Gloria Y. Kwei
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Susan A. Iliff
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Randall R. Miller
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Marjorie A. Egan
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Nathan X. Yu
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Dennis C. Dean
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Sanjeev Kumar
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Magang Shou
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Jiunn H. Lin
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Thomas A. Baillie
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Abstract

The cytochrome P-450 (CYP)3A4-mediated metabolism of diclofenac is stimulated in vitro by quinidine. A similar effect is observed in incubations with monkey liver microsomes. We describe an in vivo interaction of diclofenac and quinidine that leads to enhanced clearance of diclofenac in monkeys. After a dose of diclofenac via portal vein infusion at 0.055 mg/kg/h, steady-state systemic plasma drug concentrations in three male rhesus monkeys were 87, 104, and 32 ng/ml, respectively (control). When diclofenac was coadministered with quinidine (0.25 mg/kg/h) via the same route, the corresponding plasma diclofenac concentrations were 50, 59, and 18 ng/ml, representing 57, 56, and 56% of control values, respectively. In contrast, steady-state systemic diclofenac concentrations in the same three monkeys were elevated 1.4 to 2.5 times when the monkeys were pretreated with L-754,394 (10 mg/kg i.v.), an inhibitor of CYP3A. Further investigation indicated that the plasma protein binding (>99%) and blood/plasma ratio (0.7) of diclofenac remained unchanged in the presence of quinidine. Therefore, the decreases in plasma concentrations of diclofenac after a combined dose of diclofenac and quinidine are taken to reflect increased hepatic clearance of the drug, presumably resulting from the stimulation of CYP3A-catalyzed oxidative metabolism. Consistent with this proposed mechanism, a 2-fold increase in the formation of 5-hydroxydiclofenac derivatives was observed in monkey hepatocyte suspensions containing diclofenac and quinidine. Stimulation of diclofenac metabolism by quinidine was diminished when monkey liver microsomes were pretreated with antibodies against CYP3A. Subsequent kinetic studies indicated that theKm value for the CYP-mediated conversion of diclofenac to its 5-hydroxy derivatives was little changed (75 versus 59 μM), whereas Vmax increased 2.5-fold in the presence of quinidine. These data suggest that the catalytic capacity of monkey hepatic CYP3A toward diclofenac metabolism is enhanced by quinidine.

Footnotes

  • Send reprint requests to: Wei Tang, Ph.D., Department of Drug Metabolism, Merck & Co., P.O. Box 2000, RY80L-109, Rahway, NJ 07065. E-mail: wei_tang{at}merck.com

  • Abbreviations:
    CYP
    cytochrome P-450
    GSH
    reduced glutathione
    LC/MS/MS
    liquid chromatography/tandem mass spectrometry
    4′-OH-3′-GS-diclofenac
    4′-hydroxy-3′-(glutathion-S-yl)diclofenac
    5-OH-4-GS-diclofenac
    5-hydroxy-4-(glutathion-S-yl)diclofenac
    5-OH-6-GS-diclofenac
    5-hydroxy-6-(glutathion-S-yl)diclofenac
    TFA
    trifluoroacetic acid
    • Received June 7, 1999.
    • Accepted August 18, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 291 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 291, Issue 3
1 Dec 1999
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Research ArticleArticle

Interaction of Diclofenac and Quinidine in Monkeys: Stimulation of Diclofenac Metabolism

Wei Tang, Ralph A. Stearns, Gloria Y. Kwei, Susan A. Iliff, Randall R. Miller, Marjorie A. Egan, Nathan X. Yu, Dennis C. Dean, Sanjeev Kumar, Magang Shou, Jiunn H. Lin and Thomas A. Baillie
Journal of Pharmacology and Experimental Therapeutics December 1, 1999, 291 (3) 1068-1074;

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Research ArticleArticle

Interaction of Diclofenac and Quinidine in Monkeys: Stimulation of Diclofenac Metabolism

Wei Tang, Ralph A. Stearns, Gloria Y. Kwei, Susan A. Iliff, Randall R. Miller, Marjorie A. Egan, Nathan X. Yu, Dennis C. Dean, Sanjeev Kumar, Magang Shou, Jiunn H. Lin and Thomas A. Baillie
Journal of Pharmacology and Experimental Therapeutics December 1, 1999, 291 (3) 1068-1074;
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