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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Modulation of P450 CYP3A4-Dependent Metabolism by P-glycoprotein: Implications for P450 Phenotyping

Jens M. Baron, Lay Beng Goh, Denggao Yao, C. Roland Wolf and Thomas Friedberg
Journal of Pharmacology and Experimental Therapeutics February 2001, 296 (2) 351-358;
Jens M. Baron
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Lay Beng Goh
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Denggao Yao
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C. Roland Wolf
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Thomas Friedberg
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Abstract

Some compounds used for phenotyping of cytochrome P450s are substrates of P-glycoprotein (pgp). It is likely that in these cases, the level of pgp modulates the metabolism of in vivo probes. To address this important issue, we have analyzed the effects of pgp on CYP3A4-mediated reactions in two newly established cell lines (3A4/HR/MDR−and 3A4/HR/MDR+), which express CYP3A4 in the absence and presence of pgp, respectively. In cultured cells, the presence of pgp increased the apparent K m for the 6β-hydroxylase activity of CYP3A4 toward testosterone and cortisol by a factor of 1.7 and 4, respectively. These steroids are poor and good substrates of pgp, respectively, and cortisol 6β-hydroxylase has been frequently used as an in vivo probe for CYP3A4. Interestingly, we also found that pgp modulated the inhibition of CYP3A4-mediated metabolism by several compounds in intact cells. Although quinidine inhibited testosterone 6β-hydroxylase activity in membranes or in intact cells that expressed recombinant CYP3A4 in the absence of pgp, low concentrations of this compound increased CYP3A4 activity in intact cells that expressed pgp. These results imply that pharmacokinetic drug-drug interactions involving CYP3A4 can be influenced by pgp.

Footnotes

    • Received July 3, 2000.
    • Accepted September 27, 2000.
  • Send reprint requests to: Dr. T. Friedberg, Biomedical Research Center, University of Dundee, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK. E-mail:t.h.friedberg{at}dundee.ac.uk

  • This work was supported by a grant of the German Research Council (to J.M.B).

  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 296 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 296, Issue 2
1 Feb 2001
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Modulation of P450 CYP3A4-Dependent Metabolism by P-glycoprotein: Implications for P450 Phenotyping

Jens M. Baron, Lay Beng Goh, Denggao Yao, C. Roland Wolf and Thomas Friedberg
Journal of Pharmacology and Experimental Therapeutics February 1, 2001, 296 (2) 351-358;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Modulation of P450 CYP3A4-Dependent Metabolism by P-glycoprotein: Implications for P450 Phenotyping

Jens M. Baron, Lay Beng Goh, Denggao Yao, C. Roland Wolf and Thomas Friedberg
Journal of Pharmacology and Experimental Therapeutics February 1, 2001, 296 (2) 351-358;
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