Iida Azumi, Sasaki Eita, Yano Azusa, Tsuneyama Koichi, Fukami Tatsuki, Nakajima Miki, Yokoi Tsuyoshi
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan (A.I., E.S., A.Y., T.F., M.N., T.Y.); Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, Japan (K.T.); and Department of Drug Safety Science, Nagoya University Graduate School of Medicine, Nagoya, Japan (T.Y.).
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan (A.I., E.S., A.Y., T.F., M.N., T.Y.); Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, Japan (K.T.); and Department of Drug Safety Science, Nagoya University Graduate School of Medicine, Nagoya, Japan (T.Y.)
Drug Metab Dispos. 2015 Jul;43(7):958-68. doi: 10.1124/dmd.115.063370. Epub 2015 Apr 13.
Carbamazepine (CBZ) is widely used as an antiepileptic agent and causes rare but severe liver injury in humans. It has been generally recognized that reactive metabolites formed via the metabolic activation reaction contribute to the onset of liver injuries by several drugs. However, the role of CBZ metabolism in the development of liver injury is not fully understood. In this study, we developed a novel rat model of CBZ-induced liver injury and attempted to elucidate the associated mechanisms by focusing on the metabolism of CBZ. The repeated administration of CBZ for 5 days in combination with l-buthionine sulfoximine (BSO), a glutathione (GSH) synthesis inhibitor, resulted in increases in the plasma alanine aminotransferase (ALT) levels and centrilobular necrosis in the liver that were observed in various degrees. The CBZ and 2-hydroxy-CBZ concentrations in the plasma after the last CBZ administration were lower in the rats with high plasma ALT levels compared with those with normal plasma ALT levels, showing the possibility that the further metabolism of CBZ and/or 2-hydroxy-CBZ is associated with the liver injury. Although a single administration of CBZ did not affect the plasma ALT levels, even when cotreated with BSO, pretreatment with dexamethasone, a CYP3A inducer, increased the plasma ALT levels. In addition, the rats cotreated with troleandomycin or ketoconazole, CYP3A inhibitors, suppressed the increased plasma ALT levels. In conclusion, reactive metabolite(s) of CBZ produced by CYP3A under the GSH-depleted condition might be involved in the development of liver injury in rats.
卡马西平（CBZ）作为一种抗癫痫药物被广泛使用，在人类中会引起罕见但严重的肝损伤。人们普遍认为，通过代谢活化反应形成的反应性代谢产物会导致几种药物引发肝损伤。然而，卡马西平代谢在肝损伤发生过程中的作用尚未完全明确。在本研究中，我们建立了一种新型的卡马西平诱导肝损伤大鼠模型，并试图通过关注卡马西平的代谢来阐明相关机制。连续5天重复给予卡马西平并联合谷胱甘肽（GSH）合成抑制剂L-丁硫氨酸亚砜胺（BSO），导致血浆丙氨酸氨基转移酶（ALT）水平升高以及肝脏小叶中心坏死，且不同程度地观察到这些现象。与血浆ALT水平正常的大鼠相比，血浆ALT水平高的大鼠在最后一次给予卡马西平后血浆中卡马西平和2-羟基卡马西平的浓度较低，这表明卡马西平和/或2-羟基卡马西平的进一步代谢可能与肝损伤有关。尽管单次给予卡马西平即使与BSO联合处理也不会影响血浆ALT水平，但用CYP3A诱导剂地塞米松预处理会增加血浆ALT水平。此外，与CYP3A抑制剂三乙酰竹桃霉素或酮康唑联合处理的大鼠抑制了血浆ALT水平的升高。总之，在GSH耗竭的情况下，由CYP3A产生的卡马西平反应性代谢产物可能参与了大鼠肝损伤的发生。
