首页> 外文期刊>Journal of pharmaceutical sciences. >Pharmacokinetics of chlorzoxazone in rats with diabetes: Induction of CYP2E1 on 6-hydroxychlorzoxazone formation.
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Pharmacokinetics of chlorzoxazone in rats with diabetes: Induction of CYP2E1 on 6-hydroxychlorzoxazone formation.

机译:氯唑沙宗在糖尿病大鼠中的药代动力学:CYP2E1对6-羟基氯唑沙宗形成的诱导作用。

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Pharmacokinetic parameters of chlorzoxazone (CZX) and its main metabolite, 6-hydroxychlorzoxazone (OH-CZX), were compared after intravenous (20 mg/kg) and oral (50 mg/kg) administration of CZX in rat model of diabetes induced by alloxan (DMIA) or streptozotocin (DMIS), and their respective control rats. In both rat models of diabetes, the expression and mRNA level of CYP2E1 increased, and CZX was metabolized to OH-CZX via CYP2E1 in rats. Hence, it could be expected that formation of OH-CZX increased in both rat models of diabetes. As expected, after intravenous (80.5% and 74.4% increase in rat models of DMIA and DMIS, respectively) and oral (55.6% and 70.5% increase, respectively) administration of CZX, the AUC of OH-CZX was significantly greater than their respective control rats. Since, CZX is an intermediate hepatic extraction ratio drug, the greater AUC values of OH-CZX (the significantly faster CL(NR) of CZX) in both rat models of diabetes could be supported by significantly faster CL(int) for theformation of OH-CZX (75.9% and 129% increase for rat models of DMIA and DMIS, respectively) and significantly greater free fractions of CZX in plasma (51.9% and 58.9% increase, respectively). Also it was reported that hepatic blood flow rate was faster in male Wister rat model of DMIS.
机译:在由四氧嘧啶诱发的糖尿病大鼠模型中,静脉内(20 mg / kg)和口服(50 mg / kg)施用氯唑沙宗(CZX)及其主要代谢产物6-羟基氯唑沙宗(OH-CZX)的药代动力学参数进行了比较(DMIA)或链脲佐菌素(DMIS),以及它们各自的对照大鼠。在这两种糖尿病大鼠模型中,CYP2E1的表达和mRNA水平均升高,并且在大鼠中CZX通过CYP2E1代谢为OH-CZX。因此,可以预期在两种糖尿病大鼠模型中,OH-CZX的形成都会增加。不出所料,在静脉注射(分别在DMIA和DMIS大鼠模型中分别增加80.5%和74.4%)和口服(分别增加55.6%和70.5%)施用CZX之后,OH-CZX的AUC显着大于它们各自的对照大鼠。由于CZX是一种中度肝提取比例药物,因此在两种糖尿病大鼠模型中,OH-CZX的更大AUC值(CZX的CL(NR)明显更快)可以通过明显更快的OH形成CL(int)来支持。 -CZX(在DMIA和DMIS大鼠模型中分别增加75.9%和129%)和血浆中CZX的自由分数显着增加(分别增加51.9%和58.9%)。另外,据报道,雄性WMIS大鼠DMIS模型中肝血流速度更快。

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