A new method for measurement of (-)-sophocarpine, a candidate therapeutic for viral myocarditis, in plasma: application to a toxicokinetic study in beagle dogs
A new method for measurement of (-)-sophocarpine, a candidate therapeutic for viral myocarditis, in plasma: application to a toxicokinetic study in beagle dogs
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DOI：
10.1002/rcm.2132
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发表时间：
2005-01-01
影响因子：
2
通讯作者：
Xu, F
中科院分区：
文献类型：
--
作者：
Guo, B;Li, C;Xu, F
天然存在的生物碱 (-)-槐果碱 (SC) 已被开发为一种新型抗柯萨奇病毒药物，可用于治疗病毒性心肌炎。然而，目前尚无快速、灵敏的方法可用于确定 SC 毒性研究过程中的全身暴露。本文报道了第一种基于液相色谱串联质谱 (LC/MS/MS) 的快速、灵敏方法的开发和全面验证，用于测定血浆中的 SC。这种新的检测方法通过使用最少的样品净化程序和较短的色谱分析时间来提高样品通量。研究了生物基质对 SC 和内标 (-)-stepholidine 电离的影响，以进行方法开发和验证，并发现两种有机溶剂（甲基叔丁基醚和乙酸乙酯）用于样品制备，可产生较低的基质效应。新的分析方法用于分析从比格犬重复剂量 SC 毒性研究中获得的血浆样本。毒代动力学分析结果表明，SC的全身暴露量与剂量成正比，并且以7.5、15或30 mg/kg/天静脉SC重复治疗3个月后，未观察到SC的明显蓄积。这种灵敏且特异的 LC/MS/MS 技术可为各种生物液体中 SC 的准确定量奠定基础，用于临床前和临床药代动力学评估。版权所有 (C) 2005 John Wiley & Sons, Ltd.
The naturally occurring alkaloid (-)-sophocarpine (SC) has been developed as a novel anti-coxsackieviral agent for potential treatment of viral myocarditis. However, there is currently no rapid, sensitive method available for ascertaining systemic exposure during the course of SC toxicity studies. The development and full validation of the first rapid and sensitive method, based on liquid chromatography with tandem mass spectrometry (LC/MS/MS), for determination of SC in plasma is reported here. This new assay increases sample throughput by using minimal sample clean-up procedures and short chromatographic analysis times. The bio-matrix effect on the ionization of SC and the internal standard, (-)-stepholidine, was investigated for method development and validation, and two organic solvents (methyl tert-butyl ether and ethyl acetate) were found for sample preparation that led to low matrix effects. The new analytical method was used to analyze plasma samples obtained from a repeated-dose toxicity study of SC in beagle dogs. The results of the toxicokinetic analysis indicated that the systemic exposure to SC was proportional to the dose, and that no significant accumulation of SC was observed after 3 months of repeated treatments with intravenous SC at 7.5,15, or 30 mg/kg/day. This sensitive and specific LC/MS/MS technique can form the basis for accurate quantification of SC in various biological fluids for preclinical and clinical pharmacokinetic evaluation. Copyright (C) 2005 John Wiley & Sons, Ltd.