title: Metabolite identification of the antimalarial piperaquine in vivo using liquid chromatography-high-resolution mass spectrometry in combination with multiple data-mining tools in tandem.
abstract: 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-HRMS(n) in combination with multiple data-mining techniques in tandem can be a valuable analytical strategy for rapid metabolite profiling of drugs. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: School of Pharmaceutical Sciences, Shandong University, Jinan, China.
authors.forename: Aijuan
authors.initials: A
authors.lastname: Yang
authors.affiliation: School of Pharmaceutical Sciences, Shandong University, Jinan, China.
authors.forename: Meitong
authors.initials: M
authors.lastname: Zang
authors.affiliation: School of Pharmaceutical Sciences, Shandong University, Jinan, China.
authors.forename: Huixiang
authors.initials: H
authors.lastname: Liu
authors.affiliation: School of Pharmaceutical Sciences, Shandong University, Jinan, China.
authors.forename: Peihong
authors.initials: P
authors.lastname: Fan
authors.affiliation: School of Pharmaceutical Sciences, Shandong University, Jinan, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Xing
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000097:blood / Q000378:metabolism* / Q000652:urine; D002853:Chromatography, Liquid / Q000379:methods*; D006801:Humans; D011804:Quinolines / Q000097:blood / Q000378:metabolism* / Q000652:urine; D051381:Rats; D053719:Tandem Mass Spectrometry / Q000379:methods*; D010879:Piperazines
chemical_list: D000962:Antimalarials; D011804:Quinolines; C034759:piperaquine; D010879:Piperazines
keywords: isotope pattern filter; liquid chromatography tandem high-resolution mass spectrometry; mass defect filter; metabolites; piperaquine