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Research ArticleArticle

Diclofenac-Induced Inactivation of CYP3A4 and Its Stimulation by Quinidine

Yasuhiro Masubuchi, Atsushi Ose and Toshiharu Horie
Drug Metabolism and Disposition October 2002, 30 (10) 1143-1148; DOI: https://doi.org/10.1124/dmd.30.10.1143
Yasuhiro Masubuchi
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Atsushi Ose
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Toshiharu Horie
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Abstract

Incubation of human liver microsomes with diclofenac in the presence of NADPH resulted in a decrease in testosterone 6β-hydroxylation activity. The decrease in the activity followed time- and concentration-dependent kinetics, required oxidative metabolism, and was resistant to reduced glutathione, suggesting that diclofenac causes a mechanism-based inactivation of cytochrome P450 (P450) 3A4 (CYP3A4). The inactivation was reproduced by using microsomes from B-lymphoblastoid cell lines expressing CYP3A4 instead of human liver microsomes. No other monooxygenase activities measured as indexes of P450 enzymes; CYP2C8, CYP2C9, or CYP2C19 was inactivated by the same incubation procedure. Quinidine, a stimulant of CYP3A4-mediated diclofenac 5-hydroxylation, did not affect the inactivation of CYP3A4 assessed by testosterone 6β-hydroxylation activity but accelerated the inactivation assessed by diazepam 3-hydroxylation activity. These results supported the idea that diclofenac 5-hydroxylation is involved in the inactivation of CYP3A4 and described for the first time a stimulation of mechanism-based inactivation attributable to CYP3A4 heterotropic cooperativity. Preincubation of human liver microsomes with 5-hydroxydiclofenac instead of diclofenac did not cause the inactivation of CYP3A4, suggesting that 5-hydroxydiclofenac is not a precursor of a postulated reactive metabolite that inactivates CYP3A4, and thus 5-hydroxylation step is critical to inactivation of CYP3A4.

Footnotes

  • This work was supported in part by a grant-in-aid from the Ministry of Education, Science, and Culture of Japan.

  • Abbreviations used are::
    P450
    cytochrome P450
    GSH
    reduced glutathione
    G-6-P
    glucose 6-phosphate
    G-6-PDH
    glucose 6-phosphate dehydrogenase
    HPLC
    high-performance liquid chromatography
    • Received April 22, 2002.
    • Accepted July 15, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (10)
Drug Metabolism and Disposition
Vol. 30, Issue 10
1 Oct 2002
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Research ArticleArticle

Diclofenac-Induced Inactivation of CYP3A4 and Its Stimulation by Quinidine

Yasuhiro Masubuchi, Atsushi Ose and Toshiharu Horie
Drug Metabolism and Disposition October 1, 2002, 30 (10) 1143-1148; DOI: https://doi.org/10.1124/dmd.30.10.1143

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Research ArticleArticle

Diclofenac-Induced Inactivation of CYP3A4 and Its Stimulation by Quinidine

Yasuhiro Masubuchi, Atsushi Ose and Toshiharu Horie
Drug Metabolism and Disposition October 1, 2002, 30 (10) 1143-1148; DOI: https://doi.org/10.1124/dmd.30.10.1143
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