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Research ArticleArticle

Selective Biotransformation of the Human Immunodeficiency Virus Protease Inhibitor Saquinavir by Human Small-Intestinal Cytochrome P4503A4

Potential Contribution to High First-Pass Metabolism

Michael E. Fitzsimmons and Jerry M. Collins
Drug Metabolism and Disposition February 1997, 25 (2) 256-266;
Michael E. Fitzsimmons
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Jerry M. Collins
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Potential Contribution to High First-Pass Metabolism

Abstract

Saquinavir is a HIV1 protease inhibitor used in the treatment of patients with acquired immunodeficiency syndrome, but its use is limited by low oral bioavailability. The potential of human intestinal tissue to metabolize saquinavir was assessed in 17 different human small-intestinal microsomal preparations. Saquinavir was metabolized by human small-intestinal microsomes to numerous mono- and dihydroxylated species with KM values of 0.3–0.5 μM. The major metabolites M-2 and M-7 were single hydroxylations on the octahydro-2-(1H)-isoquinolinyl and (1,1-dimethylethyl)amino groups, respectively. Ketoconazole and troleandomycin, selective inhibitors of cytochrome P4503A4 (CYP3A4), were potent inhibitors for all oxidative metabolites of saquinavir. The cytochrome P450-selective inhibitors furafylline, fluvoxamine, sulfaphenazole, mephenytoin, quinidine, and chlorzoxazone had little inhibitory effect. All saquinavir metabolites were highly correlated with testosterone 6β-hydroxylation and with each other. Human hepatic microsomes and recombinant CYP3A4 oxidized saquinavir to the same metabolic profile observed with human small-intestinal microsomes. Indinavir, a potent HIV protease inhibitor and a substrate for human hepatic CYP3A4, was a comparatively poor substrate for human intestinal microsomes and inhibited the oxidative metabolism of saquinavir to all metabolites with a Ki of 0.2 μM. In addition, saquinavir inhibited the human, small-intestinal, microsomal CYP3A4-dependent detoxication pathway of terfenadine to its alcohol metabolite with aKi value of 0.7 μM. These data indicate that saquinavir is metabolized by human intestinal CYP3A4, that this metabolism may contribute to its poor oral bioavailability, and that combination therapy with indinavir or other protease inhibitors may attenuate its low relative bioavailability.

Footnotes

  • Send reprint requests to: Dr. Michael E. Fitzsimmons, U.S. Food and Drug Administration, Division of Clinical Pharmacology Research, 4 Research Court, Room 311, Rockville, MD 20850.

  • Abbreviations used are::
    HIV
    human immunodeficiency virus
    IC90
    inhibitory concentration of 90%
    CYP
    cytochrome P450
    HL
    human liver
    HG
    human small intestine
    ESI
    electrospray ionization
    • Received September 12, 1996.
    • Accepted November 19, 1996.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 25, Issue 2
1 Feb 1997
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Research ArticleArticle

Selective Biotransformation of the Human Immunodeficiency Virus Protease Inhibitor Saquinavir by Human Small-Intestinal Cytochrome P4503A4

Michael E. Fitzsimmons and Jerry M. Collins
Drug Metabolism and Disposition February 1, 1997, 25 (2) 256-266;

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Research ArticleArticle

Selective Biotransformation of the Human Immunodeficiency Virus Protease Inhibitor Saquinavir by Human Small-Intestinal Cytochrome P4503A4

Michael E. Fitzsimmons and Jerry M. Collins
Drug Metabolism and Disposition February 1, 1997, 25 (2) 256-266;
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