Department of Microbiology, School of Medicine, Huzhou University, Huzhou, China.
School of Pharmaceutical Sciences, Shandong University, Jinan, China.
Biomed Chromatogr. 2024 May;38(5):e5844. doi: 10.1002/bmc.5844. Epub 2024 Feb 7.
As first-line antimalarials used in the artemisinin combination therapy, artemisinin drugs exert their action inside red blood cells. However, the blood pharmacokinetic characteristics of artemisinin drugs have not been fully revealed owing to their built-in chemical instability initiated by Fe released from hemoglobin, with limited information on their metabolites. In this study, liquid chromatography tandem high-resolution mass spectrometric (LC-HRMS) methods were developed for the quantification of two representative artemisinin drugs (artemisinin, ART; dihydroartemisinin, DHA) and their respective metabolite (deoxyartemisinin, D-ART; dihydroartemisinin glucuronide, DHA-Glu) in rat blood/plasma. The blood samples were pretreated with the stabilizer (0.4 m potassium dichromate and 3% EDTA-2Na). The methods displayed excellent specificity, linearity, accuracy and precision for ART (17.7-709.2 nm) and its metabolite D-ART (18.8-751.9 nm), and the linear range was 40.0-4,000.0 nm for both DHA and DHA-Glu. The methods were successfully applied to the pharmacokinetic studies of ART and DHA in rats. The blood-to-plasma ratio was 0.8-1.5 for ART, 1.0-1.5 for D-ART, 1.2-2.2 for DHA and 0.9-1.3 for DHA-Glu, which was time dependent. The results indicated that artemisinin drugs and their metabolites showed a high but different blood-to-plasma ratio, which should be considered when optimizating their dosing regimens or evaluating their clinical outcomes.
作为青蒿素联合疗法中一线抗疟药物，青蒿素类药物在红细胞内发挥作用。然而，由于血红蛋白释放的铁引发的内在化学不稳定性，青蒿素类药物的血液药代动力学特征尚未完全揭示，其代谢物的信息也很有限。在这项研究中，开发了液相色谱串联高分辨率质谱（LC-HRMS）方法，用于定量测定两种代表性的青蒿素类药物（青蒿素，ART；双氢青蒿素，DHA）及其各自的代谢物（脱氧青蒿素，D-ART；双氢青蒿素葡萄糖醛酸苷，DHA-Glu）在大鼠血液/血浆中的浓度。血液样品用稳定剂（0.4 m 重铬酸钾和 3% EDTA-2Na）预处理。该方法对 ART（17.7-709.2nm）及其代谢物 D-ART（18.8-751.9nm）具有优异的特异性、线性、准确性和精密度，DHA 和 DHA-Glu 的线性范围分别为 40.0-4000.0nm。该方法成功应用于大鼠中 ART 和 DHA 的药代动力学研究。ART 的血-血浆比为 0.8-1.5，D-ART 为 1.0-1.5，DHA 为 1.2-2.2，DHA-Glu 为 0.9-1.3，均随时间变化。结果表明，青蒿素类药物及其代谢物具有较高但不同的血-血浆比，在优化其给药方案或评估其临床疗效时应予以考虑。
