Identification of the metabolites of ivermectin in humans.
Identification of the metabolites of ivermectin in humans.
复制标题
伊维菌素在人体内代谢产物的鉴定。
DOI：
10.1002/prp2.712
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发表时间：
2021-03
影响因子：
2.6
通讯作者：
Tarning J
中科院分区：
文献类型：
--
作者：
Tipthara P;Kobylinski KC;Godejohann M;Hanboonkunupakarn B;Roth A;Adams JH;White NJ;Jittamala P;Day NPJ;Tarning J
伊维菌素的大规模给药已被提议作为一种可能的消除疟疾工具。伊维菌素对蚊子的致死作用远远超过其生物半衰期，表明存在活性缓慢消除的代谢物。使用人肝微粒体、原代人肝细胞和口服伊维菌素的健康志愿者的全血，通过超高效液相色谱结合高分辨率质谱法来鉴定伊维菌素代谢物。通过质谱测定代谢物的分子结构并通过核磁共振验证。使用纯细胞色素 P450 酶亚型来阐明代谢途径。将伊维菌素与人肝微粒体一起孵育后，鉴定出 13 种不同的代谢物 (M1-M13)。三种（M1、M3 和 M6）是口服伊维菌素后在志愿者的微粒体、肝细胞和血液中发现的主要代谢物。 LC-MS/MS和NMR确定的化学结构表明M1是3″-O-去甲基伊维菌素，M3是4-羟甲基伊维菌素，M6是3″-O-去甲基，4-羟甲基伊维菌素。使用特征性细胞色素 P450 酶进行的代谢途径评估表明，M1、M3 和 M6 主要由 CYP3A4 产生，M1 也少量由 CYP3A5 产生。去甲基化（M1）和羟基化（M3）伊维菌素是主要的人体体内代谢物。需要进一步研究来表征这些代谢物的药代动力学特性和蚊子致死活性。使用汇集的人肝微粒体鉴定了伊维菌素 (M1-M13) 的 13 种不同的 1 期代谢物。伊维菌素的去甲基化（M1）和羟基化（M3）被证明是人类志愿者的两个主要代谢途径。
Mass drug administration of ivermectin has been proposed as a possible malaria elimination tool. Ivermectin exhibits a mosquito‐lethal effect well beyond its biological half‐life, suggesting the presence of active slowly eliminated metabolites. Human liver microsomes, primary human hepatocytes, and whole blood from healthy volunteers given oral ivermectin were used to identify ivermectin metabolites by ultra‐high performance liquid chromatography coupled with high‐resolution mass spectrometry. The molecular structures of metabolites were determined by mass spectrometry and verified by nuclear magnetic resonance. Pure cytochrome P450 enzyme isoforms were used to elucidate the metabolic pathways. Thirteen different metabolites (M1‐M13) were identified after incubation of ivermectin with human liver microsomes. Three (M1, M3, and M6) were the major metabolites found in microsomes, hepatocytes, and blood from volunteers after oral ivermectin administration. The chemical structure, defined by LC‐MS/MS and NMR, indicated that M1 is 3″‐O‐demethyl ivermectin, M3 is 4‐hydroxymethyl ivermectin, and M6 is 3″‐O‐demethyl, 4‐hydroxymethyl ivermectin. Metabolic pathway evaluations with characterized cytochrome P450 enzymes showed that M1, M3, and M6 were produced primarily by CYP3A4, and that M1 was also produced to a small extent by CYP3A5. Demethylated (M1) and hydroxylated (M3) ivermectin were the main human in vivo metabolites. Further studies are needed to characterize the pharmacokinetic properties and mosquito‐lethal activity of these metabolites. Thirteen different phase 1 metabolites of ivermectin (M1‐M13) were identified using pooled human liver microsomes. Demethylation (M1) and hydroxylation (M3) of ivermectin were demonstrated to be the two main metabolism pathways in human volunteers.
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影响因子：
3
作者：
Kobylinski KC;Foy BD;Richardson JH
通讯作者：
Richardson JH
影响因子：
3
作者：
Chaccour CJ;Kobylinski KC;Bassat Q;Bousema T;Drakeley C;Alonso P;Foy BD
通讯作者：
Foy BD
影响因子：
6.7
作者：
Kobylinski, Kevin C.;Jittamala, Podjanee;Tarning, Joel
通讯作者：
Tarning, Joel
影响因子：
7.6
作者：
Caly, Leon;Druce, Julian D;Wagstaff, Kylie M
通讯作者：
Wagstaff, Kylie M
影响因子：
2.3
作者：
Sleno, Lekha
通讯作者：
Sleno, Lekha