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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Differentiation of Gut and Hepatic First Pass Metabolism and Secretion of Saquinavir in Ported Rabbits

Patrick J. Sinko, Jeevan R. Kunta, Helen H. Usansky and Barbara A. Perry
Journal of Pharmacology and Experimental Therapeutics July 2004, 310 (1) 359-366; DOI: https://doi.org/10.1124/jpet.103.064394
Patrick J. Sinko
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Jeevan R. Kunta
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Helen H. Usansky
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Barbara A. Perry
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Abstract

The current study was performed in intestinal and vascular access ported rabbits to quantify and differentiate the components of intestinal and hepatic first pass extraction (i.e., metabolism and secretion) of saquinavir (SQV) mediated by P-glycoprotein (P-gp) and CYP3A. SQV was administered i.v. (1–5 mg/kg) or into the upper small intestine (USI) (5 mg/kg). The roles of intestinal and hepatic secretion by means of P-gp and/or metabolism by CYP3A on the first pass gastrointestinal extraction of SQV were differentiated by using N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)-ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918) (a P-gp inhibitor), midazolam (an inhibitor of CYP3A), or cyclosporine A (an inhibitor of P-gp and CYP3A). The bioavailability (BA) of SQV after USI dosing was 4%. In the presence of CYP3A and P-gp inhibitors, the BA of SQV increased 2- to 11-fold. Based on a relatively unchanged Cmax but prolonged Tmax and t1/2, P-gp and CYP3A inhibition appeared to alter SQV disposition (i.e., enhanced oral bioavailability by diminishing SQV elimination and by increasing its net intestinal absorption). In conclusion, the current results substantiate the role of the liver and, for the first time, experimentally establish an important role for the intestine in the net absorption and disposition of SQV. The results also demonstrate that changes in SQV disposition due to the modulation of metabolism and secretion were important and may potentially have considerable implications on multiple drug therapeutic regimens used in the treatment of AIDS.

Footnotes

  • The project was supported by National Institutes of Health Grant AI 42007.

  • DOI: 10.1124/jpet.103.064394.

  • ABBREVIATIONS: BA, bioavailability; IVAP, intestinal and vascular access ported; SQV, saquinavir; HIV, human immunodeficiency virus; P-gp, P-glycoprotein; PV, portal vein; USI, upper small intestine; LC, liquid chromatography; MS/MS, tandem mass spectrometry; GF120918, N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide; SPE, solid phase extraction; Foral, bioavailability after USI administration; AUC, area under plasma concentration time curve; AUC0–t, AUC to the last sampling time point; Fabs, the fraction that enters the intestinal cell; Fgw, the fraction that survives from gut wall elimination; FH, fraction escaped from hepatic extraction; EH, hepatic extraction ratio; Egw, gut wall extraction ratio; PK, pharmacokinetic; CLH, hepatic clearance; Fr, relative bioavailability; Fr(I), relative intestinal availability; SA, systemic artery; MDZ, midazolam; CsA, cyclosporine A; NZW, New Zealand White.

    • Received December 15, 2003.
    • Accepted March 2, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 310 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 310, Issue 1
1 Jul 2004
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Differentiation of Gut and Hepatic First Pass Metabolism and Secretion of Saquinavir in Ported Rabbits

Patrick J. Sinko, Jeevan R. Kunta, Helen H. Usansky and Barbara A. Perry
Journal of Pharmacology and Experimental Therapeutics July 1, 2004, 310 (1) 359-366; DOI: https://doi.org/10.1124/jpet.103.064394

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Differentiation of Gut and Hepatic First Pass Metabolism and Secretion of Saquinavir in Ported Rabbits

Patrick J. Sinko, Jeevan R. Kunta, Helen H. Usansky and Barbara A. Perry
Journal of Pharmacology and Experimental Therapeutics July 1, 2004, 310 (1) 359-366; DOI: https://doi.org/10.1124/jpet.103.064394
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