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Research ArticleArticle

Induction of P-Glycoprotein and Cytochrome P450 3A by HIV Protease Inhibitors

Liyue Huang, Stephen A. Wring, Joseph L. Woolley, Kenneth R. Brouwer, Cosette Serabjit-Singh and Joseph W. Polli
Drug Metabolism and Disposition May 2001, 29 (5) 754-760;
Liyue Huang
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Stephen A. Wring
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Joseph L. Woolley
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Kenneth R. Brouwer
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Cosette Serabjit-Singh
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Joseph W. Polli
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Abstract

P-Glycoprotein (Pgp) and cytochrome P450 3A (CYP3A) are important enzymes affecting the disposition of HIV protease inhibitors (HIV PIs). After multiple dosing experiments in rats, decreases in the plasma concentrations and area under plasma concentration-time curve (AUC) for HIV PIs have been observed. The purpose of these studies was to determine the changes in Pgp and CYP3A expression and HIV PI plasma exposure after multiple doses of HIV PIs. Male rats were orally dosed with an amprenavir prodrug (450 mg/kg/day amprenavir-equivalent) or nelfinavir (175 mg/kg/day) for 1 or 14 days. Relative to day 1, theCmax and the AUC for amprenavir at day 14 were decreased by 33 and 51%, respectively. Similarly, the plasma concentration of nelfinavir at 1 h after the last dose (Cmax) was reduced by 52% after multiple doses. Compared with controls, dosing of amprenavir for 14 days increased intestinal Pgp and hepatic CYP3A protein levels by 59 and 151%, respectively, but did not alter intestinal CYP3A protein levels. In contrast, amprenavir treatment did not result in an increase in hepatic CYP3A activity. Nelfinavir treatment increased expression of intestinal Pgp and hepatic CYP3A levels by 83 and 85%, respectively, but not hepatic Pgp or intestinal CYP3A. HIV PIs also induced Pgp expression in the LS174T human intestinal cell line. These results indicate that HIV protease inhibitors induce both intestinal Pgp and hepatic CYP3A and suggest that induction of Pgp and CYP3A is a possible mechanism reducing drug exposure after multiple doses.

Footnotes

  • Send reprint requests to: Dr. Joseph W. Polli, Bioanalysis and Drug Metabolism, Glaxo SmithKline, Inc., Rm. MAI.A3666, P.O. Box 13398, Research Triangle Park, NC 27709-3398. E-mail:JP16063{at}glaxowellcome.com

  • Abbreviations used are::
    Pgp
    P-glycoprotein
    AUC
    area under plasma concentration-time curve
    BBM
    brush border membrane
    CYP3A
    cytochrome P450 3A
    HIV PI
    human immunodeficiency virus protease inhibitor
    P450
    cytochrome P450
    HPMC
    hydroxypropylmethylcellulose
    PMSF
    phenylmethylsulfonyl fluoride
    HPLC
    high-performance liquid chromatography
    LC/MS/MS
    liquid chromatography tandem mass spectrometry
    MDR
    multidrug resistance
    DMSO
    dimethyl sulfoxide
    • Received August 14, 2000.
    • Accepted January 19, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 29 (5)
Drug Metabolism and Disposition
Vol. 29, Issue 5
1 May 2001
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Research ArticleArticle

Induction of P-Glycoprotein and Cytochrome P450 3A by HIV Protease Inhibitors

Liyue Huang, Stephen A. Wring, Joseph L. Woolley, Kenneth R. Brouwer, Cosette Serabjit-Singh and Joseph W. Polli
Drug Metabolism and Disposition May 1, 2001, 29 (5) 754-760;

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Research ArticleArticle

Induction of P-Glycoprotein and Cytochrome P450 3A by HIV Protease Inhibitors

Liyue Huang, Stephen A. Wring, Joseph L. Woolley, Kenneth R. Brouwer, Cosette Serabjit-Singh and Joseph W. Polli
Drug Metabolism and Disposition May 1, 2001, 29 (5) 754-760;
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