Abstract：
To uncover the effect of danshensu on irbesartan pharmacokinetics and its underlying mechanisms.To investigate the effect of danshensu on the pharmacokinetics of irbesartan, Sprague-Dawley rats (n = 6) were orally administered 30 mg/kg irbesartan alone (control group) or pre-treated with 160 mg/kg danshensu (experimental group). The effect of danshensu on the metabolic stability of irbesartan in RLMs was examined by LC-MS/MS method. The effect of danshensu on CYP2C9 activity was also determined.Danshensu markedly increased the AUC(0-t) (9573 ± 441 vs. 16157 ± 559 μg/L*h) and Cmax (821 ± 24 vs. 1231 ± 44 μg/L) of irbesartan. Danshensu prolonged the t1/2 (13.39 ± 0.98 vs. 16.04 ± 1.21 h) and decreased the clearance rate (2.27 ± 0.14 vs. 1.19 ± 0.10 L/h/kg) of irbesartan. Danshensu enhanced the metabolic stability of irbesartan in vitro with prolonged t1/2 (36.34 ± 11.68 vs. 48.62 ± 12.03 min) and reduced intrinsic clearance (38.14 ± 10.24 vs. 28.51 ± 9.06 μL/min/mg protein). Additionally, the IC50 value for CYP2C9 inhibition by danshensu was 35.74 μM.Danshensu enhanced systemic exposure of irbesartan by suppressing CYP2C9. The finding can also serve as a guidance for further investigation of danshensu-irbesartan interaction in clinical practice.
摘要：
1.揭示丹参素对厄贝沙坦药代动力学的影响及其机制。探讨丹参素对厄贝沙坦药代动力学的影响,Sprague-Dawley大鼠（n=6）单独口服30mg/kg厄贝沙坦（对照组）或用160mg/kg丹参素预处理（实验组）。采用LC-MS/MS法检测丹参素对厄贝沙坦在RLMs中代谢稳定性的影响。还确定了丹参素对CYP2C9活性的影响。3。丹参素显着增加AUC（0-t）（9573±441vs.16157±559μg/L*h）和Cmax（821±24vs.1231±44μg/L)厄贝沙坦。丹参素延长了t1/2（13.39±0.98vs.16.04±1.21h），并降低清除率（2.27±0.14vs.1.19±0.10L/h/kg)厄贝沙坦。丹参素增强厄贝沙坦的体外代谢稳定性，延长t1/2（36.34±11.68vs.48.62±12.03min)和降低的固有清除率(38.14±10.24vs.28.51±9.06μL/min/mg蛋白)。此外,丹参素抑制CYP2C9的IC50值为35.74μM.4。丹参素通过抑制CYP2C9增强厄贝沙坦的全身暴露。该发现也可以作为临床实践中进一步研究丹参素-厄贝沙坦相互作用的指导。
