Analyzing the Effect of Resveratrol on Pharmacokinetics of Antituberculosis Drug Bedaquiline in Rats by a Novel UPLC-MS/MS Approach

Abstract

Bedaquiline (BDQ), a diarylquinoline compound, is an inhibitor of mycobacterial ATP synthase, specifically with FDA approval as a treatment for multidrug-resistant tuberculosis (MDR-TB). M2 is the main metabolite of BDQ and is active against tuberculosis. The objective of this study was to establish and validate a sensitive and convenient ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) approach to concurrently quantify BDQ and M2 in rat plasma and to examine whether resveratrol, a CYP3A4 inhibitor, could influence the pharmacokinetics of BDQ and M2 in rats. Plasma samples containing the internal standard (IS) linezolid were formulated by adding acetonitrile for a simple one-step protein precipitation, and the analytes in samples were quantified by the UPLC-MS/MS method. BDQ and M2 were successfully calibrated in the ranges of 0.5-1000 and 1.0-200 ng/mL, where the lower limit of quantification (LLOQ) was 0.5 and 1.0 ng/mL, respectively. The precisions and accuracies of BDQ and M2 were in compliance with the FDA analytical standards. Recoveries and matrix effects of the analytes were satisfactory, and the analytes remained stable under four different temperatures and conditions. The well-validated UPLC-MS/MS method was successfully applied to the study of the food-drug interaction in rats. Remarkably, resveratrol increased the level of exposure of BDQ. Furthermore, the effect of resveratrol on the metabolism of BDQ and M2 needs further clinical studies.

Figure 1

Chemical structures and mass spectra of BDQ (A), M2 (B), and linezolid (IS, C) in the present study.

Figure 2

Representative MRM chromatograms of BDQ, M2 and IS in SD rat sample: blank plasma (A), blank plasma spiked with standard solutions (B) and real plasma sample collected from a rat following oral administration of 20 mg/kg BDQ after 1 h (C).

Figure 3

Mean plasma concentration–time curves of BDQ and M2 in male SD rats after oral administration of 20 mg/kg BDQ alone or with 50 mg/kg resveratrol (n = 5, Mean ± SD).