化学
色谱法
蛋白质沉淀
利福平
药代动力学
治疗药物监测
甲酸
吡嗪酰胺
高效液相色谱法
异烟肼
醋酸铵
代谢物
药理学
肺结核
抗生素
生物化学
医学
病理
作者
Marta Karaźniewicz−Łada,Katarzyna Kosicka-Noworzyń,Prakruti Rao,Nisha Modi,Yingda L. Xie,Scott K Heysell,Leonid Kagan
标识
DOI:10.1016/j.jpba.2023.115650
摘要
Successful tuberculosis (TB) therapy requires achieving sufficient exposure to multiple drugs. Limited stability of several first-line anti-TB drugs might compromise reliable therapeutic drug monitoring (TDM). We developed and validated a sensitive and selective UPLC-MS/MS method for simultaneous quantification of isoniazid (INH), pyrazinamide (PZA), rifampicin (RIF), its metabolite 25-desacetylrifampicin and degradation products: rifampicin quinone and 3-formyl-rifampicin. Analysis was completed from a very small plasma volume (20 µL) using only protein precipitation with methanol. Chromatographic separation was achieved on a Kinetex Polar C18 column (2.6 µm; 150 × 3 mm) with a mobile phase consisting of 5 mM ammonium acetate and acetonitrile, both containing 0.1 % formic acid, in gradient elution. The analytes were detected using a positive ionization mode by multiple reaction monitoring. The LLOQ for RIF and its degradation products was 0.1 µg/mL, 0.05 µg/mL for INH, and 0.2 µg/mL for PZA. The method was validated based on the FDA guidance. The application of the method was confirmed in the analysis of RIF, INH, and PZA, as well as RIF metabolism/degradation products in plasma samples of patients with TB. Based on the detailed stability study of the analyzed compounds at various storage conditions, we proposed recommendations for handling the plasma and serum samples in TDM and other pharmacokinetic studies.
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