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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Inhibition of Organic Anion Transporting Polypeptide-Mediated Hepatic Uptake Is the Major Determinant in the Pharmacokinetic Interaction between Bosentan and Cyclosporin A in the Rat

Alexander Treiber, Ralph Schneiter, Stephane Delahaye and Martine Clozel
Journal of Pharmacology and Experimental Therapeutics March 2004, 308 (3) 1121-1129; DOI: https://doi.org/10.1124/jpet.103.061614
Alexander Treiber
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Ralph Schneiter
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Stephane Delahaye
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Martine Clozel
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Abstract

In clinical trials, a significant interaction between the endothelin receptor antagonist bosentan and the immunosuppressant cyclosporin A was observed, which could not be rationalized in terms of inhibition of drug-metabolizing enzymes. We present here a study performed in rats investigating the mechanisms underlying this interaction, including the inhibition of active drug transport processes as part of the gastrointestinal absorption and disposition into the liver. In vitro, the majority of bosentan uptake into liver cells was shown to depend on active transport and to be efficiently inhibited by cyclosporin A. All known members of the organic anion transporting polypeptide (oatp) transport protein family expressed in rat liver, i.e., oatp1, oatp2, and oatp4, were shown to be involved in the uptake of bosentan. Results from both series of experiments point to inhibition of active bosentan uptake into the liver by cyclosporin A as the major underlying mechanism for this pharmacokinetic interaction that is in line with reports on other oatp-transported drugs. Significant contributions of other mechanisms such as inhibition of mdr1-mediated drug efflux during gastrointestinal absorption, inhibition of bosentan metabolism, or inhibition of hepatobiliary excretion seemed to be unlikely. The interaction between bosentan and cyclosporin A is a rare example of a pharmacokinetic interaction, which can mostly be attributed to the inhibition of transport processes in the liver. It also demonstrates that inhibition of uptake into the liver might become rate-limiting in the overall elimination process even for compounds whose clearance is dependent on metabolism. The relevance of these findings in the rat for clinical use remains to be explored. It is, however, clear that inhibition of CYP3A4-mediated metabolism by cyclosporin A alone is insufficient to explain the increased bosentan concentrations and that inhibition of hepatocellular uptake offers an attractive mechanistic alternative also in human.

Footnotes

  • DOI: 10.1124/jpet.103.061614.

  • ABBREVIATIONS: P450, cytochrome P450; oatp/OATP, organic anion transporting polypeptide (in rat and human); FBS, fetal bovine serum; CCK-8, cholecystokinin; LC-MS/MS, triple stage mass spectrometry coupled to liquid chromatography; AUC, area under the plasma concentration-time curve; AUMC, area under the first moment-time curve; CL, systemic plasma clearance; F, absolute bioavailability; λz, terminal elimination rate constant; Vss, volume of distribution at steady state; Ro 48-5033, 4-(2-hydroxy-1,1-dimethylethyl)-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-[2,2′]bipyrimidinyl-4-yl]-benzenesulfonamide; Ro 47-8634, 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-hydroxyphenoxy)-[2,2′]bipyrimidinyl-4-yl]-benzenesulfonamide; Ro 64-1056, 4-(2-hydroxy-1,1-dimethylethyl)-N-[6-(2-hydroxyethoxy)-5-(2-hydroxyphenoxy)-[2,2′]bipyrimidinyl-4-yl]benzenesulfonamide.

    • Received October 14, 2003.
    • Accepted November 10, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 308 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 308, Issue 3
1 Mar 2004
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Inhibition of Organic Anion Transporting Polypeptide-Mediated Hepatic Uptake Is the Major Determinant in the Pharmacokinetic Interaction between Bosentan and Cyclosporin A in the Rat

Alexander Treiber, Ralph Schneiter, Stephane Delahaye and Martine Clozel
Journal of Pharmacology and Experimental Therapeutics March 1, 2004, 308 (3) 1121-1129; DOI: https://doi.org/10.1124/jpet.103.061614

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Inhibition of Organic Anion Transporting Polypeptide-Mediated Hepatic Uptake Is the Major Determinant in the Pharmacokinetic Interaction between Bosentan and Cyclosporin A in the Rat

Alexander Treiber, Ralph Schneiter, Stephane Delahaye and Martine Clozel
Journal of Pharmacology and Experimental Therapeutics March 1, 2004, 308 (3) 1121-1129; DOI: https://doi.org/10.1124/jpet.103.061614
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