一种验证的LC-MS/MS方法用于未结合的里法丁量化,揭示了非线性血蛋白结合和成人和患有结核病的儿童之间的可比的自由分数
Wenmei Qiao1,2, Mutong Fang1,3, Miaona Liu1,2
1The Third People's Hospital of Shenzhen, The Second Affiliated Hospital of Southern University of Science and Technology, National Clinical Research Center for Infectious Diseases, Shenzhen, Guangdong, 518112, People's Republic of China.
European journal of drug metabolism and pharmacokinetics
|January 29, 2026
概括
这项研究开发了一种敏感的LC-MS/MS方法,用于监测结核病患者的自由里法丁 (RFPT) 度. 直接测量自由RFPT对于优化治疗和预防毒性至关重要,因为总度不能完全反映药物效应.
科学领域:
- 药理学 药理学是指药理学的学科.
- 分析化学 分析化学
- 临床医学 临床医学
背景情况:
- 治疗药物监测 (TDM) 通常依赖于药物总度 (Ct),这可能不会准确地反映如利法丁 (RFPT) 等高蛋白结合药物的药理效应.
- 自由药物度 (Cf) 是有效性和毒性的更好指标,特别是在结核病 (TB) 患者中,结合蛋白质的变化.
- 现有的RFPT测定方法缺乏用于常规监测自由度所需的灵敏度.
研究的目的:
- 开发和验证一种灵敏的液体染色学-并联质谱法 (LC-MS/MS) 方法,用于量化人体血中的自由RFPT (Cf).
- 评估成人和儿童结核病患者的自由和总RFPT度 (Cf和Ct) 之间的相关性.
- 评估Cf监测对优化RFPT治疗和最大限度地减少肝毒性的临床实用性.
主要方法:
- 采用已验证的LC-MS/MS方法,使用离心超 (CF-UF) 来分离自由的RFPT.
- 为了准确量化,使用了同位素内部标准 (里法丁-d8).
- 该方法在特异性,线性,准确性,精度,矩阵效应和稳定性方面得到了验证,其下限量化值 (LLOQ) 为3.00 ng/mL.
- 从58名结核病患者 (成人和儿童) 的临床样本中分析了Cf,Ct,白蛋白和生物化学参数.
主要成果:
- 这种LC-MS/MS方法表现出极好的线性 (R2=0.9999),准确性 (93.11-102.67%) 和精度 (RSD ≤7.40%).
- 在Cf和Ct之间观察到非线性关系.
- 虽然总RFPT度 (Ct) 在成年人中明显高于儿童,但自由RFPT度 (Cf) 和自由分数在两组之间没有显著差异.
结论:
- 开发的LC-MS/MS方法是快速的,灵敏的,适合于无常规的RFPT TDM.
- 由于非线性Ct-Cf关系和蛋白质结合的潜在变化,对Cf的直接监测至关重要.
- 成人和儿童中类似的自由分数表明,以TDM为指导的剂量调整可能是必要的,以优化疗效和最大限度地降低毒性,因为单独Ct可能无法普遍适用.
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