Abstract Context Ligustrazine and valsartan are commonly used drugs in the treatment of cardiac and cardiovascular disease. Objective The interaction between ligustrazine and valsartan was studied to investigate the effect of ligustrazine on the pharmacokinetics of valsartan. Materials and methods The pharmacokinetics of valsartan (10 mg/kg) was investigated in Sprague–Dawley rats divided into three groups (with the pretreatment of 4 or 10 mg/kg/day ligustrazine for 10 days and without the pretreatment of ligustrazine as control) of six rats each. The in vitro experiments in rat liver microsomes were performed to explore the effect of ligustrazine on the metabolic stability of valsartan. Results Ligustrazine changed the pharmacokinetic profile of valsartan. In the presence of 4 mg/kg ligustrazine, the AUC(0–t) (385.37 ± 93.05 versus 851.64 ± 104.26 μg/L*h), t1/2 (5.46 ± 0.93 versus 6.34 ± 1.25 h), and Cmax (62.64 ± 9.09 versus 83.87 ± 6.15 μg/L) of valsartan was significantly decreased, and the clearance rate was increased from 10.92 ± 1.521 to 25.76 ± 6.24 L/h/kg and similar changes were observed in the group with 10 mg/kg ligustrazine (p < 0.05). The metabolic stability of valsartan was also decreased by ligustrazine as the half-life of valsartan in rat liver microsomes decreased from 37.12 ± 4.06 to 33.48 ± 3.56 min and the intrinsic clearance rate increased from 37.34 ± 3.84 to 41.40 ± 4.32 μL/min/mg protein (p < 0.05). Discussion and conclusions Ligustrazine promoted the metabolism of valsartan via activating CYP3A4. The co-administration of ligustrazine and valsartan should be taken into account.

中文翻译：

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川芎嗪与缬沙坦在大鼠体内的药代动力学相互作用研究及其潜在机制

摘要 背景川芎嗪和缬沙坦是治疗心脏和心血管疾病的常用药物。目的研究川芎嗪与缬沙坦的相互作用，探讨川芎嗪对缬沙坦药代动力学的影响。材料和方法 在 Sprague-Dawley 大鼠中研究缬沙坦 (10 mg/kg) 的药代动力学，分为三组（预处理 4 或 10 mg/kg/天川芎嗪 10 天，未预处理川芎嗪作为对照）每只六只老鼠。通过大鼠肝微粒体体外实验，探讨川芎嗪对缬沙坦代谢稳定性的影响。结果川芎嗪改变了缬沙坦的药代动力学特征。在 4 mg/kg 川芎嗪的存在下，AUC(0–t) (385.37 ± 93.05 vs 851.64 ± 104。26 μg/L*h)、t1/2 (5.46 ± 0.93 vs 6.34 ± 1.25 h) 和 Cmax (62.64 ± 9.09 vs 83.87 ± 6.15 μg/L) 显着降低，清除率从 10.92 增加± 1.521 至 25.76 ± 6.24 L/h/kg 和类似的变化在具有 10 mg/kg 川芎嗪的组中观察到 (p < 0.05)。缬沙坦的代谢稳定性也被川芎嗪降低，因为缬沙坦在大鼠肝微粒体中的半衰期从 37.12 ± 4.06 降至 33.48 ± 3.56 min，内在清除率从 37.34 ± 3.84 增至 41.40 ± 4.32 mg/min蛋白质（p < 0.05）。讨论与结论川芎嗪通过激活CYP3A4促进缬沙坦的代谢。应考虑同时服用川芎嗪和缬沙坦。09 vs 83.87 ± 6.15 μg/L) 缬沙坦显着降低，清除率从 10.92 ± 1.521 增加到 25.76 ± 6.24 L/h/kg，在 10 mg/kg 川芎嗪组中观察到类似变化（p < 0.05)。缬沙坦的代谢稳定性也被川芎嗪降低，因为缬沙坦在大鼠肝微粒体中的半衰期从 37.12 ± 4.06 降至 33.48 ± 3.56 min，内在清除率从 37.34 ± 3.84 增至 41.40 ± 4.32 mg/min蛋白质（p < 0.05）。讨论与结论川芎嗪通过激活CYP3A4促进缬沙坦的代谢。应考虑同时服用川芎嗪和缬沙坦。09 vs 83.87 ± 6.15 μg/L) 缬沙坦显着降低，清除率从 10.92 ± 1.521 增加到 25.76 ± 6.24 L/h/kg，在 10 mg/kg 川芎嗪组中观察到类似变化（p < 0.05)。缬沙坦的代谢稳定性也被川芎嗪降低，因为缬沙坦在大鼠肝微粒体中的半衰期从 37.12 ± 4.06 降至 33.48 ± 3.56 min，内在清除率从 37.34 ± 3.84 增至 41.40 ± 4.32 mg/min蛋白质（p < 0.05）。讨论与结论川芎嗪通过激活CYP3A4促进缬沙坦的代谢。应考虑同时服用川芎嗪和缬沙坦。在含有 10 mg/kg 川芎嗪的组中观察到 24 L/h/kg 和类似的变化（p < 0.05）。缬沙坦的代谢稳定性也被川芎嗪降低，因为缬沙坦在大鼠肝微粒体中的半衰期从 37.12 ± 4.06 降低到 33.48 ± 3.56 分钟，内在清除率从 37.34 ± 3.84 增加到 41.40 ± 4.32 毫克/分钟蛋白质（p < 0.05）。讨论与结论川芎嗪通过激活CYP3A4促进缬沙坦的代谢。应考虑同时服用川芎嗪和缬沙坦。在含有 10 mg/kg 川芎嗪的组中观察到 24 L/h/kg 和类似的变化（p < 0.05）。缬沙坦的代谢稳定性也被川芎嗪降低，因为缬沙坦在大鼠肝微粒体中的半衰期从 37.12 ± 4.06 降至 33.48 ± 3.56 min，内在清除率从 37.34 ± 3.84 增至 41.40 ± 4.32 mg/min蛋白质（p < 0.05）。讨论与结论川芎嗪通过激活CYP3A4促进缬沙坦的代谢。应考虑同时服用川芎嗪和缬沙坦。34 ± 3.84 至 41.40 ± 4.32 μL/min/mg 蛋白质（p < 0.05）。讨论与结论川芎嗪通过激活CYP3A4促进缬沙坦的代谢。应考虑同时服用川芎嗪和缬沙坦。34 ± 3.84 至 41.40 ± 4.32 μL/min/mg 蛋白质（p < 0.05）。讨论与结论川芎嗪通过激活CYP3A4促进缬沙坦的代谢。应考虑同时服用川芎嗪和缬沙坦。