Ye Yun, Chen Zhe, Shen Yuxin, Wu Hualu, Xu Ren-Ai, Zhou Chen-Jian
Beilun District People's Hospital, Ningbo 315800, Zhejiang, China.
The Third Affiliated Hospital of Shanghai University (Wenzhou People's Hospital), Wenzhou 325000, Zhejiang, China.
ACS Omega. 2024 Nov 25;9(49):48650-48656. doi: 10.1021/acsomega.4c07752. eCollection 2024 Dec 10.
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.
贝达喹啉（BDQ）是一种二芳基喹啉化合物，是分枝杆菌ATP合酶的抑制剂，尤其已获美国食品药品监督管理局（FDA）批准用于治疗耐多药结核病（MDR-TB）。M2是BDQ的主要代谢产物，对结核病有活性。本研究的目的是建立并验证一种灵敏且便捷的超高效液相色谱串联质谱法（UPLC-MS/MS），以同时定量大鼠血浆中的BDQ和M2，并研究CYP3A4抑制剂白藜芦醇是否会影响BDQ和M2在大鼠体内的药代动力学。含有内标（IS）利奈唑胺的血浆样品通过加入乙腈进行简单的一步蛋白沉淀来制备，样品中的分析物通过UPLC-MS/MS方法进行定量。BDQ和M2在0.5 - 1000 ng/mL和1.0 - 200 ng/mL范围内成功校准，其中定量下限（LLOQ）分别为0.5和1.0 ng/mL。BDQ和M2的精密度和准确度符合FDA分析标准。分析物的回收率和基质效应令人满意，并且分析物在四种不同温度和条件下保持稳定。经过充分验证的UPLC-MS/MS方法成功应用于大鼠的食物 - 药物相互作用研究。值得注意的是，白藜芦醇增加了BDQ的暴露水平。此外，白藜芦醇对BDQ和M2代谢的影响需要进一步的临床研究。
