Jiao Weijie, Zhao Xu, Wu Guiyue, Zhang Xiangyun, Wu Hong, Cui Yinglin
Department of Pharmacy, Henan Province Hospital of Traditional Chinese Medicine, Zhengzhou, Henan Province, China.
Laboratory of Cell Imaging, Henan University of Chinese Medicine, Zhengzhou, Henan Province, China.
Drug Test Anal. 2020 Jun;12(6):827-835. doi: 10.1002/dta.2777. Epub 2020 Feb 19.
Lumiracoxib is a selective cyclooxygenase-2 inhibitor, which has been reported to cause rare but severe liver injury. Considering that lumiracoxib has a carboxylic group in the molecule, glucuronidation to form acylglucuronide would be one of the possible mechanisms of lumiracoxib-induced liver injury. The aim of this study was to identify the metabolites of lumiracoxib that were formed via acyl-glucuronidation in human liver microsomes using glutathione (GSH) and N-acetyl-lysine (NAL) as trapping agents by liquid chromatography combined with high resolution mass spectrometry. The structures of the detected metabolites were identified by their accurate masses, fragment ions, and retention times. Under the current conditions, eight lumiracoxib associated metabolites were identified. With the presence of UDPGA, lumiracoxib was biotransformed into lumiracoxib-1-O-acylglucuronide (M1) and 4'-hydroxyl-lumiracoxib-1-O-acylglucuronide (M2), both of which were reactive and prone to react with GSH to form drug-S-acyl-GSH adducts (M3 and M4) through transacylation. In addition to reaction with GSH, the formed 1-O-acylglucuronides were chemically unstable (T = 1.5 h in phosphate buffer) and rearranged to 2-, 3-, and/or 4-isomers, which further underwent ring-opening to form aldehyde derivatives and then reacted with NAL to yield Schiff base derivatives (M5-M8). The present study provides a clear bioactivation profile of lumiracoxib through acyl glucuronidation, which would be one of the mechanisms attributed to liver injury caused by lumiracoxib.
鲁米昔布是一种选择性环氧化酶-2抑制剂，据报道可引起罕见但严重的肝损伤。鉴于鲁米昔布分子中含有羧基，葡萄糖醛酸化形成酰基葡萄糖醛酸可能是鲁米昔布诱导肝损伤的一种潜在机制。本研究的目的是通过液相色谱结合高分辨率质谱，以谷胱甘肽（GSH）和N-乙酰赖氨酸（NAL）作为捕获剂，鉴定人肝微粒体中通过酰基葡萄糖醛酸化形成的鲁米昔布代谢产物。通过精确质量、碎片离子和保留时间确定检测到的代谢产物的结构。在当前条件下，鉴定出了8种与鲁米昔布相关的代谢产物。在尿苷二磷酸葡萄糖醛酸（UDPGA）存在的情况下，鲁米昔布被生物转化为鲁米昔布-1-O-酰基葡萄糖醛酸（M1）和4'-羟基-鲁米昔布-1-O-酰基葡萄糖醛酸（M2），这两种产物都具有反应活性，易于与GSH通过转酰化反应形成药物-S-酰基-GSH加合物（M3和M4）。除了与GSH反应外，形成的1-O-酰基葡萄糖醛酸化学性质不稳定（在磷酸盐缓冲液中的半衰期T = 1.5小时），会重排为2-、3-和/或4-异构体，这些异构体进一步开环形成醛衍生物，然后与NAL反应生成席夫碱衍生物（M5-M8）。本研究通过酰基葡萄糖醛酸化明确了鲁米昔布的生物活化过程，这可能是鲁米昔布导致肝损伤的机制之一。
