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In vivo and in vitro studies exploring the pharmacokinetic interaction between bosentan, a dual endothelin receptor antagonist, and glyburide
Author(s) -
Giersbergen Paul L. M.,
Treiber Alexander,
Clozel Martine,
Bodin Frédéric,
Dingemanse Jasper
Publication year - 2002
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1067/mcp.2002.122473
Subject(s) - bosentan , endothelin receptor antagonist , pharmacology , in vivo , endothelin receptor , pharmacokinetics , antagonist , in vitro , medicine , receptor antagonist , chemistry , receptor , biology , biochemistry , microbiology and biotechnology
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