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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Assessing Safety and Efficacy of Directed P-Glycoprotein Inhibition to Improve the Pharmacokinetic Properties of Saquinavir Coadministered with Ritonavir

Maarten T. Huisman, Johan W. Smit, Hugh R. Wiltshire, Jos H. Beijnen and Alfred H. Schinkel
Journal of Pharmacology and Experimental Therapeutics February 2003, 304 (2) 596-602; DOI: https://doi.org/10.1124/jpet.102.044388
Maarten T. Huisman
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Johan W. Smit
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Hugh R. Wiltshire
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Jos H. Beijnen
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Alfred H. Schinkel
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Abstract

Using a mouse model, we tested the effects of in vivo P-glycoprotein inhibition to enhance the oral uptake and penetration into pharmacological sanctuary sites of the human immunodeficiency virus protease inhibitor (HPI) saquinavir. The HPI ritonavir is frequently coadministered with saquinavir to improve saquinavir plasma levels since it strongly reduces the cytochrome P450 3A4-mediated metabolism of saquinavir. Previously, we demonstrated that ritonavir is not an efficient P-glycoprotein inhibitor in vivo, evidenced by the limited oral uptake of saquinavir and its penetration into brain and fetus. Increasing drug concentrations in these sites using more effective P-gp inhibitors might improve therapy but could also lead to toxicity. We orally coadministered ritonavir and saquinavir to mice, with or without the potent P-glycoprotein inhibitorN-(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). Upon GF120918 coadministration, two of seven P-glycoprotein-deficient animals died. Using a decreased ritonavir dose, GF120918 coadministration led to a 4.4-fold increase in the saquinavir plasma area under the curve in wild-type mice, whereas no such effect was observed in P-glycoprotein-deficient mice. Despite the decreased ritonavir dose, all mice did suffer from impaired gastric emptying. Including GF120918 in a multiple (bidaily) dosing regimen, we found continued accumulation of saquinavir in brain over several days, resulting in 10-fold higher levels compared with vehicle-treated mice. Transient ritonavir-related neurotoxicity, however, was observed after the fourth and final drug dosing. Clinical attempts to efficiently inhibit P-glycoprotein function for improved HPI disposition may therefore be feasible, but they should be performed without ritonavir and monitored carefully for unexpected toxicities.

Footnotes

  • This study was funded in part by the AIDS Fonds (The Netherlands) Project 4011.

  • DOI: 10.1124/jpet.102.044388

  • Abbreviations:
    HIV
    human immunodeficiency virus
    HPI
    HIV protease inhibitor
    AIDS
    acquired immunodeficiency syndrome
    P-gp P-glycoprotein
    CNS, central nervous system
    GF120918
    1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide
    HPLC
    high-performance liquid chromatography
    AUC
    area under the curve
    • Received September 11, 2002.
    • Accepted October 22, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 304 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 304, Issue 2
1 Feb 2003
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Assessing Safety and Efficacy of Directed P-Glycoprotein Inhibition to Improve the Pharmacokinetic Properties of Saquinavir Coadministered with Ritonavir

Maarten T. Huisman, Johan W. Smit, Hugh R. Wiltshire, Jos H. Beijnen and Alfred H. Schinkel
Journal of Pharmacology and Experimental Therapeutics February 1, 2003, 304 (2) 596-602; DOI: https://doi.org/10.1124/jpet.102.044388

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Assessing Safety and Efficacy of Directed P-Glycoprotein Inhibition to Improve the Pharmacokinetic Properties of Saquinavir Coadministered with Ritonavir

Maarten T. Huisman, Johan W. Smit, Hugh R. Wiltshire, Jos H. Beijnen and Alfred H. Schinkel
Journal of Pharmacology and Experimental Therapeutics February 1, 2003, 304 (2) 596-602; DOI: https://doi.org/10.1124/jpet.102.044388
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