标题：Metabolite identification of the antimalarial piperaquine in vivo using liquid chromatography-high-resolution mass spectrometry in combination with multiple data-mining tools in tandem
作者：Yang, Aijuan; Zang, Meitong; Liu, Huixiang; Fan, Peihong; Xing, Jie
作者机构：[Yang, Aijuan; Zang, Meitong; Liu, Huixiang; Fan, Peihong; Xing, Jie] Shandong Univ, Sch Pharmaceut Sci, Jinan, Peoples R China.
通讯作者地址：[Xing, J]Shandong Univ, Sch Pharmaceut Sci, Jinan, Peoples R China.
关键词：piperaquine; metabolites; liquid chromatography tandem high-resolution; mass spectrometry; mass defect filter; isotope pattern filter
摘要：Artemisinin-based combination therapy is widely used for the treatment of uncomplicated Plasmodium falciparum malaria, and piperaquine (PQ) is one of important partner drugs. The pharmacokinetics of PQ is characterized by a low clearance and a large volume of distribution; however, metabolism of PQ has not been thoroughly investigated. In this work, the metabolite profiling of PQ in human and rat was studied using liquid chromatography tandem high-resolution LTQ-Orbitrap mass spectrometry (HRMS). The biological samples were pretreated by solid-phase extraction. Data processes were carried out using multiple data-mining techniques in tandem, i.e., isotope pattern filter followed by mass defect filter. A total of six metabolites (M1-M6) were identified for PQ in human (plasma and urine) and rat (plasma, urine and bile). Three reported metabolites were also found in this study, which included N-oxidation (M1, M2) and carboxylic products (M3). The subsequent N-oxidation of M3 resulted in a new metabolite M4 detected in urine and bile samples. A new metabolic pathway N-dealkylation was found for PQ in human and rat, leading to two new metabolites (M5 and M6). This study demonstrated that LC-HRMSn in combination with multiple data-mining techniques in tandem can be a valuable analytical strategy for rapid metabolite profiling of drugs. Copyright (c) 2016 John Wiley & Sons, Ltd.