Kang Ping, Dalvie Deepak, Smith Evan, Renner Matt
Pharmacokinetics Dynamics and Metabolism, Research Analytical, Pfizer Global Research and Development, 10724 Science Center Drive, San Diego, California 92121, USA.
Chem Res Toxicol. 2009 Jan;22(1):106-17. doi: 10.1021/tx8002356.
Lumiracoxib (Prexige; 2-[(2-fluoro-6-chlorophenyl)amino]-5-methyl-benzeneacetic acid) is a cyclooxygenase-2 selective inhibitor for the symptomatic treatment of osteoarthritis. Recently, the drug has been withdrawn in several countries due to serious liver side effects. Li et al. recently have shown that lumiracoxib is bioactivated to a proposed quinone imine that is trapped by N-acetylcysteine (NAC) to form two NAC adducts in human and rat liver microsomal incubations. The current study demonstrated that the lumiracoxib metabolite 4'-hydroxylumiracoxib (M5) can also be bioactivated by peroxidases such as horseradish peroxidase, myeloperoxidase, and prostaglandin H synthases. Efforts were also made to identify GSH adducts formed by P450s in human liver microsomal incubations of lumiracoxib. We herein report the detection and characterization of mono-, di-, tri-, and tetra-GSH adducts in these oxidizing systems. Most of the conjugates were generated as a result of bioactivation of M5 by both peroxidases and P450s. Quinone imine (M15) and two GSH-conjugated quinone imines (M17 and M18) were identified as intermediates in the formation of these conjugates. The latter two were formed through sequential elimination of the fluorine and chlorine groups of GSH-conjugated M15. An additional GSH adduct, which appeared to be formed directly from parent, was only observed in human liver microsomal incubations. A mechanism was proposed for the bioactivation of lumiracoxib and the formation of the observed GSH adducts. These results suggest that bioactivation of lumiracoxib and M5 may result in GSH depletion, covalent binding to proteins, and oxidative stress and may potentially lead to hepatotoxicity.
鲁米昔布（普瑞昔布；2-[(2-氟-6-氯苯基)氨基]-5-甲基苯乙酸）是一种用于骨关节炎症状治疗的环氧化酶-2选择性抑制剂。最近，该药物因严重的肝脏副作用已在多个国家撤市。李等人最近表明，鲁米昔布在人和大鼠肝微粒体孵育中被生物激活生成一种推测的醌亚胺，该醌亚胺被N-乙酰半胱氨酸（NAC）捕获形成两种NAC加合物。当前研究表明，鲁米昔布代谢物4'-羟基鲁米昔布（M5）也可被辣根过氧化物酶、髓过氧化物酶和前列腺素H合酶等过氧化物酶生物激活。研究人员还致力于鉴定鲁米昔布在人肝微粒体孵育中由细胞色素P450形成的谷胱甘肽（GSH）加合物。我们在此报告在这些氧化系统中检测和鉴定出的单、二、三、四GSH加合物。大多数缀合物是M5被过氧化物酶和细胞色素P450生物激活的结果。醌亚胺（M15）和两种GSH共轭醌亚胺（M17和M18）被鉴定为这些缀合物形成过程中的中间体。后两者是通过依次消除GSH共轭M15的氟和氯基团形成的。一种似乎直接由母体形成的额外GSH加合物仅在人肝微粒体孵育中观察到。提出了鲁米昔布生物激活及所观察到的GSH加合物形成的机制。这些结果表明，鲁米昔布和M5的生物激活可能导致GSH耗竭、与蛋白质共价结合以及氧化应激，并可能潜在地导致肝毒性。
