Inhibitory effect of carvedilol on bedaquiline metabolism in vitro and in vivo.

Bedaquiline has recently been approved for the treatment of multidrug-resistant tuberculosis. Carvedilol is a cardiovascular medication extensively used in the treatment of heart failure and hypertension. In this study, Sprague-Dawley rats, rat liver microsomes (RLM), human liver microsomes (HLM), and recombinant human CYP3A4 were used to explore the effect of carvedilol on the metabolism of bedaquiline. Ultra-performance liquid chromatography-tandem mass spectrometry was used to facilitate the quantification of the analyte concentrations. In vitro, carvedilol did not exhibit time-dependent inhibition of bedaquiline, which aligns with the half-maximal inhibitory concentration (IC50) shift results. The IC50 values of carvedilol were 15.35 ± 0.43 µM in RLM, 7.55 ± 0.74 µM in HLM, and 0.79 ± 0.05 µM in CYP3A4. Besides, the inhibition type of carvedilol was found to be mixed, un-competitive, and mixed in RLM, HLM, and CYP3A4, respectively. In vivo, the co-administration of carvedilol with bedaquiline resulted in a significant increase in the area under the plasma concentration-time curve (AUC)(0 - t), AUC(0 - ∞), and Cmax of bedaquiline while decreasing its CLz/F. Lay summary: Carvedilol could inhibit the metabolism of bedaquiline in vitro and in vivo, with different mechanisms in different enzymatic reaction systems. Hence, caution should be exercised when combining bedaquiline with carvedilol.