Bosentan, a dual endothelin receptor antagonist, activates the pregnane X nuclear receptor

Abstract

Recent clinical studies have shown that bosentan, a dual endothelin receptor antagonist, decreases the exposure to various substrates of cytochrome P450 (CYP) isoenzymes 2C9 and 3A4. When bosentan and glibenclamide were given concomitantly to healthy subjects, the plasma concentrations of both compounds decreased suggesting that glibenclamide also has enzyme-inducing properties [1]. The aim of the study was to investigate if bosentan, its metabolites and glibenclamide can activate the pregnane X receptor (PXR), a nuclear receptor that regulates the transcription of CYP3A4 [2]. CV-1 monkey kidney cells were transiently transfected with a luciferase reporter plasmid containing three copies of the ER6 response element (PXRE) of CYP3A4, and an expression plasmid for human PXR (hPXR). The cells were then incubated with the test compounds at varying concentrations and the activity of luciferase determined. At a concentration of 25 μm, bosentan, Ro 47-8634 and glibenclamide but not the other two metabolites of bosentan, Ro 48-5033 and Ro 64-1056 activated PXR (Figure 1). Figure 1 Effect of bosentan, its metabolites and glibenclamide on PXR activity. Data represent mean ± s.d. of 3 experiments. An EC50 of 19.9 μm was determined for bosentan whereas rifampicin had an EC50 value of 1.9 μm. Co-incubation of sub-maximal but clinically relevant concentrations of bosentan (1 μm) and glibenclamide (0.5 to 5 μm) resulted in a more pronounced activation of PXR than with each compound alone. The effects of both compounds were additive, however, no synergism was detected. The findings are consistent with the observation that in man rifampicin is a more potent inducer than bosentan. Furthermore, they provide a molecular mechanism for the interactions observed between bosentan and several drugs.