PK-PD, Toxicology and Formulation Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Jammu, India.
Academy of Scientific and Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Jammu, India; Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India.
J Chromatogr B Analyt Technol Biomed Life Sci. 2019 Apr 1;1112:48-55. doi: 10.1016/j.jchromb.2019.02.022. Epub 2019 Feb 22.
A continuous effort has been given to find out a new drug that is effective against tuberculosis (TB) from both susceptible and resistant strains of Mycobacterium tuberculosis. Bedaquiline represents a recently approved anti-TB drug, which has a unique mechanism of action to fight against multi drug resistance (MDR). Some severe side effects and drug-drug interactions are associated with the treatment of bedaquiline. Moreover, World Health Organisation (WHO) has also been provided guidelines in the year of 2013 for the use of bedaquiline and encourages additional investigation into it. Hence, the pharmacokinetics of bedaquiline upon coadministration with the drug has to be explored in the preclinical model and for which a liquid chromatography tandem mass spectrometry (LC-MS/MS) based bioanalytical method for quantitation of bedaquiline will be useful. A simple, sensitive and rapid LC-MS/MS method was developed, validated and successfully applied to drug interactions of bedaquiline upon coadministration with cytochrome P450 3A4 (CYP3A4) inducers/inhibitors orally in Wistar rats. Results reveal that ciprofloxacin and fluconazole have marked effect to hinder the pharmacokinetics of bedaquiline but isoniazid, verapamil and carbamazepine have no significant effect on bedaquiline pharmacokinetics. Overall, this new bioanalytical method for estimation of bedaquiline in rat plasma was found to be helpful to assess the pharmacokinetics of bedaquiline and very much useful for evaluation of preclinical drug-drug interaction before considering costly and perilous clinical exploration.
一直以来，人们都在努力寻找一种新的药物，以有效对抗结核分枝杆菌（Mycobacterium tuberculosis）的敏感和耐药菌株。贝达喹啉是一种最近批准的抗结核药物，它具有独特的作用机制，可对抗多药耐药性（MDR）。贝达喹啉的治疗存在一些严重的副作用和药物相互作用。此外，世界卫生组织（WHO）也在 2013 年提供了贝达喹啉使用指南，并鼓励对其进行进一步研究。因此，必须在临床前模型中探索贝达喹啉与药物同时给药时的药代动力学，为此，基于液相色谱-串联质谱（LC-MS/MS）的贝达喹啉定量生物分析方法将是有用的。已经开发、验证并成功应用于 LC-MS/MS 方法，用于检测同时给予 Wistar 大鼠 CYP3A4（CYP3A4）诱导剂/抑制剂时贝达喹啉的药物相互作用。结果表明，环丙沙星和氟康唑对贝达喹啉的药代动力学有显著影响，但异烟肼、维拉帕米和卡马西平对贝达喹啉的药代动力学没有显著影响。总的来说，这种新的用于评估大鼠血浆中贝达喹啉的生物分析方法有助于评估贝达喹啉的药代动力学，并且在考虑昂贵且危险的临床探索之前，对于评估临床前药物相互作用非常有用。
