Bosentan, a dual endothelin receptor antagonist, is indicated for the treatment of patients with pulmonary arterial hypertension (PAH).

Clinical Pharmacology of Bosentan, a Dual Endothelin Receptor Antagonist

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.

http://jpet.aspetjournals.org/content/jpet/early/2003/11/14/jpet.103.061614.full.pdf

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.

Background

In a clinical trial with patients with chronic heart failure, a higher incidence ofelevated levels of liver transaminases was observed during concomitant treatment with bosentan, a dual endothelin receptor antagonist, and glyburide (INN, glibenclamide), a sulfonylurea-type antidiabetic drug, than with treatment withbosentan alone. This study was conducted to investigate a possible pharmacokinetic interaction between bosentan and glyburide.



Methods

In a randomized, 2-way crossover study, 12 healthy volunteers received treatments A and B. Treatment A consisted of 125 mg bosentan twice a day for 10 days plus concomitant 2.5 mg glyburide twice a day on days 6 to 10. Treatment B consisted of 2.5 mg glyburide twice a day for 10 days plus concomitant 125 mg bosentan twice a day on days 6 to 10. Plasma concentrations of bosentan and its metabolites and of glyburide were measured on days 5 and 10 of treatment A and treatment B, respectively.



Results

Bosentan reduced the area under the concentration-versus-time curve of glyburide approximately 40% (P < .05). Glyburide decreased the area under the concentration-versus-time curve of bosentan and its metabolites 20% to 30% (P < .05). Results of in vitro experiments showed that glyburide is metabolized bycytochrome P450 (CYP) 2C9, 2C19, and 3A4. No interaction was observed on the level of serum protein binding.



Conclusions

The plasma levels of both bosentan and glyburide were reduced after concomitant administration. This finding is consistent with a CYP3A4-inducing potential of both drugs. The observed pharmacodynamic interaction between bosentan and glyburide in patients with chronic heart failure cannot be explained by a pharmacokinetic interaction.



Clinical Pharmacology & Therapeutics (2002) 71, 253–262; doi: 10.1067/mcp.2002.122473

In vivo and in vitro studies exploring the pharmacokinetic interaction between bosentan, a dual endothelin receptor antagonist, and glyburide.

Effects of liquid post-column addition in electrospray ionization performance in supercritical fluid chromatography–mass spectrometry

Background: In vitro, bosentan has been shown to be a mild inducer of cytochrome P450 (CYP) 2C9 and 3A4. Purpose: To investigate in vivo the mutual pharmacokinetic interactions between bosentan and simvastatin, a CYP3A4 substrate. Methods: Nine healthy male subjects were treated in a three-period randomised crossover study with: (A) bosentan 125mg twice daily for 5.5 days; (B) simvastatin 40mg once daily for 6 days; and (C) bosentan 125mg twice daily and simvastatin 40mg once daily for 5.5 and 6 days, respectively. Plasma concentration-time profiles of bosentan and its metabolites (treatments A and C) and simvastatin and β-hydroxyacid simvastatin (treatments B and C) were determined on day 6. Results: Steady-state conditions for bosentan and its metabolites were attained on day 4 of treatment. The pharmacokinetic parameters of bosentan and its metabolites were not influenced by concomitant treatment with simvastatin: areas under the plasma concentration-time curve over one administration interval of 12 hours (AUCτ) [geometric mean and 95% CI] were 4586 (3719–5656) and 4928 (3945–6156) μg · h/L. In contrast, bosentan significantly reduced exposure to simvastatin and β-hydroxyacid simvastatin by 34 and 46%, respectively. AUC> values for simvastatin were 30.5 (23.1–40.2) and 20.0 (15.9–25.1) μg · h/L and for β-hydroxyacid simvastatin 43.0 (32.1–57.8) and 23.4 (16.7–32.6) μg · h/L in treatments B and C, respectively. Conclusion: Concomitant treatment with bosentan reduces the exposure to simvastatin and β-hydroxyacid simvastatin by approximately 40%, indicating that in vivo bosentan is also a mild inducer of CYP3A4.

Investigation of the mutual pharmacokinetic interactions between bosentan, a dual endothelin receptor antagonist, and simvastatin.

Simultaneous determination of bosentan and its three major metabolites in various biological matrices and species using narrow bore liquid chromatography with ion spray tandem mass spectrometric detection.

Determination of the renin inhibitor Ro 42-5892 in human plasma by automated pre-column derivatization, reversed-phase high-performance liquid chromatographic separation and electrochemical detection after post-column irradiation.

Determination of the partial benzodiazepine receptor agonist Ro 16-6028 in plasma by capillary gas chromatography with nitrogen-selective detection after conversion into the ethyl ester derivative.

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Papers

Simultaneous determination of bosentan and its three major metabolites in various biological matrices and species using narrow bore liquid chromatography with ion spray tandem mass spectrometric detection.

Determination of the renin inhibitor Ro 42-5892 in human plasma by automated pre-column derivatization, reversed-phase high-performance liquid chromatographic separation and electrochemical detection after post-column irradiation.

Determination of the partial benzodiazepine receptor agonist Ro 16-6028 in plasma by capillary gas chromatography with nitrogen-selective detection after conversion into the ethyl ester derivative.