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首页> 外文期刊>Journal of mass spectrometry: JMS >Rapid identification of phase I and II metabolites of artemisinin antimalarials using LTQ-Orbitrap hybrid mass spectrometer in combination with online hydrogen/deuterium exchange technique
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Rapid identification of phase I and II metabolites of artemisinin antimalarials using LTQ-Orbitrap hybrid mass spectrometer in combination with online hydrogen/deuterium exchange technique

机译：LTQ-Orbitrap混合质谱仪结合在线氢/氘交换技术快速鉴定青蒿素抗疟药的I和II期代谢物

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Artemisinin drugs have become the first-line antimalarials in areas of multi-drug resistance. However, monotherapy with artemisinin drugs results in comparatively high recrudescence rates. Autoinduction of CYP-mediated metabolism, resulting in reduced exposure, has been supposed to be the underlying mechanism. To better understand the autoinduction of artemisinin drugs, we evaluated the biotransformation of artemisinin, also known as Qing-hao-su (QHS), and its active derivative dihydroartemisinin (DHA) in vitro and in vivo, using LTQ-Orbitrap hybrid mass spectrometer in conjunction with online hydrogen (H)/deuterium (D) exchange high-resolution (HR)-LC/MS (mass spectrometry) for rapid structural characterization. The LC separation was improved allowing the separation of QHS parent drugs and their metabolites from their diastereomers. Thirteen phase I metabolites of QHS have been identified in liver microsomal incubates, rat urine, bile and plasma, including six deoxyhydroxylated metabolites, five hydroxylated metabolites, one dihydroxylated metabolite and deoxyartemisinin. Twelve phase II metabolites of QHS were detected in rat bile, urine and plasma. DHA underwent similar metabolic pathways, and 13 phase I metabolites and 3 phase II metabolites were detected. Accurate mass data were obtained in both full-scan and MS/MS mode to support assignments of metabolite structures. Online H/D exchange LC-HR/MS experiments provided additional evidence in differentiating deoxydihydroxylated metabolites from mono-hydroxylated metabolites. The results showed that the main phase I metabolites of artemisinin drugs are hydroxylated and deoxyl products, and they will undergo subsequent phase II glucuronidation processes. This study also demonstrated the effectiveness of online H/D exchange LC-HR/MS~n technique in rapid identification of drug metabolites.
机译：青蒿素药物已成为多药耐药性领域的一线抗疟药。但是，使用青蒿素药物的单一疗法会导致较高的复发率。 CYP介导的代谢的自动诱导（导致暴露减少）被认为是其潜在机制。为了更好地了解青蒿素药物的自动诱导作用，我们使用LTQ-Orbitrap混合质谱仪在体外和体内评估了青蒿素（也称为青蒿素（QHS））及其活性衍生物双氢青蒿素（DHA）的生物转化。结合在线氢（H）/氘（D）交换高分辨率（HR）-LC / MS（质谱），可进行快速结构表征。改进了LC分离，可从其非对映异构体中分离QHS母体药物及其代谢物。在肝脏微粒体温育，大鼠尿液，胆汁和血浆中已鉴定出13种QHS I期代谢物，包括6种脱氧羟基代谢物，5种羟基化代谢物，一种二羟基代谢物和脱氧青蒿素。在大鼠胆汁，尿液和血浆中检测到12种QHS II期代谢产物。 DHA经历了相似的代谢途径，并且检测到13种I期代谢物和3种II期代谢物。在全扫描和MS / MS模式下均获得了准确的质量数据，以支持代谢物结构的分配。在线H / D交换LC-HR / MS实验为区分脱氧二羟基代谢物和单羟基代谢物提供了更多证据。结果表明，青蒿素药物的主要I相代谢产物是羟基化和脱氧产物，它们将经历随后的II期葡萄糖醛酸化过程。这项研究还证明了在线H / D交换LC-HR / MS〜n技术在快速鉴定药物代谢物中的有效性。

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