Mild hypothermia decreases the total clearance of glibenclamide after low dose administration in rats
Mild hypothermia decreases the total clearance of glibenclamide after low dose administration in rats
复制标题
轻度低温降低大鼠低剂量给药后格列本脲的总清除率
DOI：
10.1016/j.neulet.2015.12.035
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发表时间：
2016
影响因子：
2.5
通讯作者：
Pan Suyue
中科院分区：
文献类型：
--
作者：
Li Xing;Ji Zhong;Gu Yong;Hu Yafang;Huang Kaibin;Pan Suyue
背景与目的小剂量格列本脲对不同的中枢神经系统疾病具有多效保护作用。此前，我们已经证明轻度低温可以增强格列本脲在培养的皮质神经元细胞中的功效。本研究旨在通过细胞色素P450 2C 9（CYP 2C 9）代谢途径评价亚低温对低剂量格列本脲在大鼠体内药代动力学的影响。在温度稳定后10 min静脉给予格列本脲（33 μg/kg）或双氯芬酸（10 mg/kg，用于评估参与格列本脲和双氯芬酸在肝脏中代谢的CYP 2C 9活性的探针药物）。在9个不同的时间点收集血浆样品。结果与常温组相比，亚低温组格列本脲和双氯芬酸的总清除率明显降低（16.00 ± 4.1-6.72 ± 2.1 mL/min/kg;p< 0.01），半衰期略长的趋势不显著（1.64 ± 0.34-2.71 ± 1.7 h，p= 0.157）。低温组血药浓度-时间曲线下面积（AUClast）增加（33.2 ± 11-77.8 ± 18 h ng/mL，p< 0.01）。亚低温降低了格列本脲的总清除率（10.33 ± 1.53-7.20 ± 1.66 mL/min/kg，p< 0.01），表明CYP 2C 9的活性在低温下受到损害。格列本脲的临床应用应考虑低温的影响。
Background and purposeLow dose glibenclamide exhibits pleiotropic protective effects in different central nervous system diseases. Previously, we have shown that mild hypothermia enhanced the efficacy of glibenclamide in the cultured cortical neuronal cells. This study aims to evaluate the impact of mild hypothermia on the pharmacokinetics of low dose glibenclamide in rats via its cytochrome P450 2C9 (CYP2C9) metabolic pathway.MethodsMale Sprague-Dawley rats were maintained at 37 °C (normothermic group) or cooled to 33 °C (hypothermic group). Glibenclamide (33 μg/kg) or diclofenac (10 mg/kg, a probe drug for assessing the activity of CYP2C9 which involves in glibenclamide and diclofenac metabolism in liver) were intravenously administered at 10 min after stabilization of temperature. Plasma samples were collected at 9 different time points. Glibenclamide and diclofenac in sera were separated by liquid chromatography and quantified with tandem mass spectrometry.ResultsCompared with normothermia, mild hypothermia significantly decreased the total clearance of glibenclamide (16.00 ± 4.1–6.72 ± 2.1 mL/min/kg;p< 0.01), and there was a non-significant trend in a slightly higher half-life, (1.64 ± 0.34–2.71 ± 1.7 h,p= 0.157). Area under the plasma concentration versus time curve (AUClast) in the hypothermic group was increased (33.2 ± 11–77.8 ± 18 h ng/mL,p< 0.01). Moreover, mild hypothermia reduced the total clearance of diclofenac (10.33 ± 1.53–7.20 ± 1.66 mL/min/kg,p< 0.01), indicating that the CYP2C9 activity was compromised in reduced temperature.ConclusionMild hypothermia reduced the total clearance of glibenclamide, probably via mediating the activity of CYP2C9. The impact of hypothermia in clinical application of glibenclamide should be considered.