In vivo and in vitro studies exploring the pharmacokinetic interaction between bosentan, a dual endothelin receptor antagonist, and glyburide.
BACKGROUND
In a clinical trial with patients with chronic heart failure, a higher incidence of elevated 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 with bosentan 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 by cytochrome 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.
van Giersbergen
Paul L M
PL
Department of Preclinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland. paul.vangiersbergen@actelion.com
Treiber
Alexander
A
Clozel
Martine
M
Bodin
Frédéric
F
Dingemanse
Jasper
J
D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D019540:Area Under Curve; D001667:Binding, Competitive; D000077300:Bosentan; D018592:Cross-Over Studies; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004338:Drug Combinations; D004347:Drug Interactions / Q000502:physiology; D065128:Endothelin Receptor Antagonists; D005260:Female; D005905:Glyburide / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D017466:Receptors, Endothelin / Q000378:metabolism; D013449:Sulfonamides / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*
D004338:Drug Combinations; D065128:Endothelin Receptor Antagonists; D007004:Hypoglycemic Agents; D007527:Isoenzymes; D017466:Receptors, Endothelin; D013449:Sulfonamides; D003577:Cytochrome P-450 Enzyme System; D000077300:Bosentan; D005905:Glyburide