Work

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

Year: 2025

Type: article

Abstract: 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.

Source: PeerJ

DOI: 10.7717/peerj.19313

Authors: Qingqing Li, Wanshu Li, Jie Chen, Hangjuan Lin, Cixia Zhou

Institutions: Zhejiang Chinese Medical University, First Affiliated Hospital of Wenzhou Medical University

Language: English

Topic: Pharmacogenetics and Drug Metabolism

Subfield: Pharmacology

Field: Pharmacology, Toxicology and Pharmaceutics

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $1,395