Chronic administration of caderofloxacin, a new fluoroquinolone, increases hepatic CYP2E1 expression and activity in rats
Chronic administration of caderofloxacin, a new fluoroquinolone, increases hepatic CYP2E1 expression and activity in rats
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长期服用卡德罗沙星（一种新型氟喹诺酮类药物）可增加大鼠肝脏 CYP2E1 的表达和活性
DOI：
10.1038/aps.2015.160
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发表时间：
2016
影响因子：
8.2
通讯作者：
Liu Xiao-dong
中科院分区：
文献类型：
--
作者：
Liu Li;Miao Ming-xing;Zhong Ze-yu;Xu Ping;Chen Yang;Liu Xiao-dong
目的：卡德罗沙星是一种新型氟喹诺酮类药物，目前正在中国进行Ⅲ期临床试验。在这里，我们检查了卡德罗沙星对大鼠肝细胞色素 P450 (CYP450) 亚型的影响以及卡德罗沙星与共同给药药物相互作用的潜力。 方法：雄性大鼠每天用卡德罗沙星（9 mg/kg，ig）治疗一次或两次，连续 14 天。使用 6 种探针（咪达唑仑、右美沙芬、奥美拉唑、茶碱、氯唑沙宗和双氯芬酸）的“混合物”在第 0 天（卡德罗沙星暴露前）和第 15 天（暴露后）评估卡德罗沙星对 CYP3A、2D6、2C19、1A2、2E1 和 2C9 的影响。卡德罗沙星暴露）。使用卡德罗沙星治疗的大鼠的肝微粒体来评估 CYP2E1 活性和氯唑沙宗代谢。分别采用RT-PCR和Western blotting分析肝微粒体中CYP2E1 mRNA和蛋白的表达。结果：卡德罗沙星给药14天显着增加了肝CYP2E1的活性，导致氯唑沙宗的代谢增强。体外微粒体研究证实CYP2E1是参与氯唑沙宗代谢的主要代谢酶，卡德罗沙星14天给药显着增加肝微粒体中CYP2E1的活性，导致6-羟基氯唑沙宗的形成增加。此外，卡德罗沙星给药14天显着增加肝微粒体中CYP2E1 mRNA和蛋白的表达，这与药代动力学结果一致。结论：卡德罗沙星给药14天可以诱导大鼠肝CYP2E1的表达和活性。当给予卡德罗沙星时，应考虑由 CYP2E1 诱导介导的潜在药物相互作用。
Aim:Caderofloxacin is a new fluoroquinolone that is under phase III clinical trials in China. Here we examined the effects of caderofloxacin on rat hepatic cytochrome P450 (CYP450) isoforms as well as the potential of caderofloxacin interacting with co-administered drugs.Methods:Male rats were treated with caderofloxacin (9 mg/kg, ig) once or twice daily for 14 consecutive days. The effects of caderofloxacin on CYP3A, 2D6, 2C19, 1A2, 2E1 and 2C9 were evaluated using a “cocktail” of 6 probes (midazolam, dextromethorphan, omeprazole, theophylline, chlorzoxazone and diclofenac) injected on d 0 (prior to caderofloxacin exposure) and d 15 (after caderofloxacin exposure). Hepatic microsomes from the caderofloxacin-treated rats were used to assess CYP2E1 activity and chlorzoxazone metabolism. The expression of CYP2E1 mRNA and protein in hepatic microsomes was analyzed with RT-PCR and Western blotting, respectively.Results:Fourteen-day administration of caderofloxacin significantly increased the activity of hepatic CYP2E1, leading to enhanced metabolism of chlorzoxazone. In vitro microsomal study confirmed that CYP2E1 was a major metabolic enzyme involved in chlorzoxazone metabolism, and the 14-d administration of caderofloxacin significantly increased the activity of CYP2E1 in hepatic microsomes, resulting in increased formation of 6-hydroxychlorzoxazone. Furthermore, the 14-d administration of caderofloxacin significantly increased the expression of CYP2E1 mRNA and protein in liver microsomes, which was consistent with the pharmacokinetic results.Conclusion:Fourteen-day administration of caderofloxacin can induce the expression and activity of hepatic CYP2E1 in rats. When caderofloxacin is administered, a potential drug-drug interaction mediated by CYP2E1 induction should be considered.