Inhibitory effect of carvedilol on bedaquiline metabolism <i>in vitro</i> and <i>in vivo</i>

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. <i>In vitro,</i> 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. <i>In vivo</i>, the co-administration of carvedilol with bedaquiline resulted in a significant increase in the area under the plasma concentration-time curve (AUC)_{(0 - <i>t</i>)}, AUC_{(0 - ∞),} and C_max of bedaquiline while decreasing its CL_z/F. <b>Lay summary</b>: Carvedilol could inhibit the metabolism of bedaquiline <i>in vitro</i> and <i>in vivo</i>, with different mechanisms in different enzymatic reaction systems. Hence, caution should be exercised when combining bedaquiline with carvedilol.