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Research ArticleArticle

Effects of Ketoconazole on the Intestinal Metabolism, Transport and Oral Bioavailability of K02, a Novel Vinylsulfone Peptidomimetic Cysteine Protease Inhibitor and a P450 3A, P-Glycoprotein Dual Substrate, in Male Sprague-Dawley Rats

Yuanchao Zhang, Yunsheng Hsieh, Takashi Izumi, Emil T. Lin and Leslie Z. Benet
Journal of Pharmacology and Experimental Therapeutics October 1998, 287 (1) 246-252;
Yuanchao Zhang
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Yunsheng Hsieh
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Takashi Izumi
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Emil T. Lin
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Leslie Z. Benet
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Abstract

We investigated the effects of ketoconazole on the oral bioavailability of morpholine-urea-phenylalanine-homophenylalanine-vinylsulfone-phenyl (K02), a vinylsulfone peptidomimetic cysteine protease inhibitor, and a P450 3A (CYP3A) and P-glycoprotein dual substrate, in male Sprague-Dawley rats, so as to evaluate the roles of CYP3A and P-gp in K02 disposition. Male Sprague-Dawley rats (8–10 wk old,n = 3–6) were administered a single dose of K02 (10 mg/kg) i.v. or (30 mg/kg) p.o. with or without a concomitant oral dose of ketoconazole (20 mg/kg). Blood samples were collected from 2 min to 8 h after administration through a implanted jugular vein cannula. K02 plasma concentrations were determined by liquid chromatography/mass spectrometer/mass spectrometer analysis. Ketoconazole markedly raised the area under the curve of orally administered K02 from 9.4 ± 4.4 to 102 ± 24 mg · min/liter and decreased K02 oral plasma clearance from 3810 ± 1620 to 306 ± 60 ml/min/kg. With concomitant ketoconazole dosing, the changes of AUC of i.v. administered K02 (from 94 ± 17 to 107 ± 14 mg · min/liter) and clearance (from 110 ± 22 to 95 ± 13 ml/min/kg) were not significant, although K02 oral bioavailability increased from 2.9 ± 1.4 to 31.0 ± 7.5% (P < .001). In summary, ketoconazole, a dual inhibitor of CYP3A and P-glycoprotein, can effectively increase K02 oral bioavailability by inhibiting the CYP3A/P-gp absorption barrier in the small intestine.

Footnotes

  • Send reprint requests to: Dr. Leslie Z. Benet, Department of Biopharmaceutical Sciences, School of Pharmacy, University of California, San Francisco, CA 94143-0446.

  • ↵1 This work was supported by National Institutes of Health Grant CA 72006.

  • Abbreviations:
    K02
    morpholine-urea-phenylalanine-homophenylalanine-vinylsulfone-phenyl
    CYP
    cytochrome P450
    P-gp
    P-glycoprotein
    MDR
    multidrug resistance
    ABC
    ATP-binding cassette
    IC50
    50% inhibitory concentration
    MDCK
    Madin-Darby canine kidney cells
    AUC
    area under curve
    CL
    clearance
    F
    oral drug bioavailability
    MAT
    mean absorption time
    MRT
    mean resident time
    Tmax
    peak time
    Vss
    volume of distribution at steady state
    HPLC
    high-performance liquid chromatography
    • Received January 6, 1998.
    • Accepted May 16, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 287, Issue 1
1 Oct 1998
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Effects of Ketoconazole on the Intestinal Metabolism, Transport and Oral Bioavailability of K02, a Novel Vinylsulfone Peptidomimetic Cysteine Protease Inhibitor and a P450 3A, P-Glycoprotein Dual Substrate, in Male Sprague-Dawley Rats
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Research ArticleArticle

Effects of Ketoconazole on the Intestinal Metabolism, Transport and Oral Bioavailability of K02, a Novel Vinylsulfone Peptidomimetic Cysteine Protease Inhibitor and a P450 3A, P-Glycoprotein Dual Substrate, in Male Sprague-Dawley Rats

Yuanchao Zhang, Yunsheng Hsieh, Takashi Izumi, Emil T. Lin and Leslie Z. Benet
Journal of Pharmacology and Experimental Therapeutics October 1, 1998, 287 (1) 246-252;

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Research ArticleArticle

Effects of Ketoconazole on the Intestinal Metabolism, Transport and Oral Bioavailability of K02, a Novel Vinylsulfone Peptidomimetic Cysteine Protease Inhibitor and a P450 3A, P-Glycoprotein Dual Substrate, in Male Sprague-Dawley Rats

Yuanchao Zhang, Yunsheng Hsieh, Takashi Izumi, Emil T. Lin and Leslie Z. Benet
Journal of Pharmacology and Experimental Therapeutics October 1, 1998, 287 (1) 246-252;
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