Metabolism of primaquine in normal human volunteers: investigation of phase I and phase II metabolites from plasma and urine using ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry.
Metabolism of primaquine in normal human volunteers: investigation of phase I and phase II metabolites from plasma and urine using ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry.
复制标题
DOI：
10.1186/s12936-018-2433-z
复制
发表时间：
2018-08-13
期刊：
影响因子：
3
通讯作者：
Walker LA
中科院分区：
文献类型：
--
作者：
Avula B;Tekwani BL;Chaurasiya ND;Fasinu P;Dhammika Nanayakkara NP;Bhandara Herath HMT;Wang YH;Bae JY;Khan SI;Elsohly MA;McChesney JD;Zimmerman PA;Khan IA;Walker LA
伯氨喹（PQ）是一种8-氨基喹啉，是美国食品和药物管理局批准的唯一一种用于根治和预防间日疟原虫感染复发的药物。了解PQ的代谢对于了解该药物的疗效和溶血毒性至关重要。最近对原代人肝细胞的体外研究有助于开发超高效液相色谱-高分辨率质谱（UHPLC-QToF-MS）方法，用于同时测定药物代谢I相和II相途径产生的PQ及其代谢产物。对这些方法进行了进一步优化，并应用于对接受45 mg PQ单次给药的健康人类志愿者的血浆和尿液中的PQ代谢物进行表型分析。通过MetaboLynx使用LC-MS/MS裂解模式预测代谢物的鉴别。采用适当的标准品确认选定的代谢产物。除PQ和羧基PQ（cPQ）（主要血浆代谢物）外，在人血浆和尿液中还鉴别出34种其他代谢物。基于这些代谢物，PQ在人体内通过三种途径代谢。途径1涉及PQ的直接葡糖苷酸/葡萄糖/氨基甲酸酯/乙酸酯结合。途径2涉及喹啉环上不同位置的羟基化（可能是细胞色素P450介导的），可能是单羟基化、二羟基化甚至三羟基化，随后是羟基化代谢物的葡糖苷酸结合。途径3涉及单胺氧化酶催化的PQ氧化脱氨，导致PQ-醛、PQ醇和cPQ的形成，这些物质通过额外的I相羟基化和/或II相葡糖苷酸结合进一步代谢。这种方法和这些发现增强了我们的理解，并提供了人类PQ代谢途径的全面观点。这些将推进不同人群中不同治疗方案的PQ代谢的临床研究，并了解这些在PQ疗效和安全性结局中的作用及其与代谢酶多态性的可能关系。本文的在线版本（10.1186/s12936-018-2433-z）包含补充材料，可供授权用户使用。
Primaquine (PQ), an 8-aminoquinoline, is the only drug approved by the United States Food and Drug Administration for radical cure and prevention of relapse in Plasmodium vivax infections. Knowledge of the metabolism of PQ is critical for understanding the therapeutic efficacy and hemolytic toxicity of this drug. Recent in vitro studies with primary human hepatocytes have been useful for developing the ultra high-performance liquid chromatography coupled with high-resolution mass spectrometric (UHPLC-QToF-MS) methods for simultaneous determination of PQ and its metabolites generated through phase I and phase II pathways for drug metabolism. These methods were further optimized and applied for phenotyping PQ metabolites from plasma and urine from healthy human volunteers treated with single 45 mg dose of PQ. Identity of the metabolites was predicted by MetaboLynx using LC–MS/MS fragmentation patterns. Selected metabolites were confirmed with appropriate standards. Besides PQ and carboxy PQ (cPQ), the major plasma metabolite, thirty-four additional metabolites were identified in human plasma and urine. Based on these metabolites, PQ is viewed as metabolized in humans via three pathways. Pathway 1 involves direct glucuronide/glucose/carbamate/acetate conjugation of PQ. Pathway 2 involves hydroxylation (likely cytochrome P450-mediated) at different positions on the quinoline ring, with mono-, di-, or even tri-hydroxylations possible, and subsequent glucuronide conjugation of the hydroxylated metabolites. Pathway 3 involves the monoamine oxidase catalyzed oxidative deamination of PQ resulting in formation of PQ-aldehyde, PQ alcohol and cPQ, which are further metabolized through additional phase I hydroxylations and/or phase II glucuronide conjugations. This approach and these findings augment our understanding and provide comprehensive view of pathways for PQ metabolism in humans. These will advance the clinical studies of PQ metabolism in different populations for different therapeutic regimens and an understanding of the role these play in PQ efficacy and safety outcomes, and their possible relation to metabolizing enzyme polymorphisms. The online version of this article (10.1186/s12936-018-2433-z) contains supplementary material, which is available to authorized users.
登录
查看更多内容
影响因子：
5.7
作者：
Chu CS;White NJ
通讯作者：
White NJ
影响因子：
5.6
作者：
Gómez-Manzo S;Marcial-Quino J;Vanoye-Carlo A;Serrano-Posada H;Ortega-Cuellar D;González-Valdez A;Castillo-Rodríguez RA;Hernández-Ochoa B;Sierra-Palacios E;Rodríguez-Bustamante E;Arreguin-Espinosa R
通讯作者：
Arreguin-Espinosa R
影响因子：
3.8
作者：
Ganesan, Shobana;Tekwani, Babu L.;Walker, Larry A.
通讯作者：
Walker, Larry A.
影响因子：
2.3
作者：
Avula, Bharathi;Tekwani, Babu L.;Walker, Larry A.
通讯作者：
Walker, Larry A.
影响因子：
3
作者：
Brasil LW;Rodrigues-Soares F;Santoro AB;Almeida ACG;Kühn A;Ramasawmy R;Lacerda MVG;Monteiro WM;Suarez-Kurtz G
通讯作者：
Suarez-Kurtz G