大鼠服用丹酚酸B合用匹伐他汀后药动学和肝细胞摄取能力的改变

In vivo Pharmacokinetics of salvianolic acid B combined with pitavastatin and uptaking of salvianolic acid B in hepatocytes of rats

目的研究大鼠服用丹酚酸B合用匹伐他汀后药动学及肝细胞摄取能力的改变。方法将SD雄性大鼠随机分为两组,每组6只,实验一组单用丹酚酸B(2.5 g/kg)给药;另一组丹酚酸B合用匹伐他汀(0.5 mg/kg)。两药合用时先丹酚酸B后匹伐他汀相继灌胃,间隔15 min,眼球静脉取血,探讨有机阴离子转运多肽(organic anion transporting polypeptides,OATP)底物匹伐他汀对丹酚酸B的药动学影响。然后,游离大鼠原代肝细胞,考察匹伐他汀对大鼠原代肝细胞摄取丹酚酸B的影响。结果丹酚酸合用匹伐他汀后,丹酚酸B的药动学特性发生明显变化,AUC(0-t)、AUC(0-∞)和Cmax分别增加了54.63%、69.72%、50.56%。随着匹伐他汀浓度增加,其对大鼠原代肝细胞摄取丹酚酸B的抑制作用逐渐增强,IC50为(5.21±1.68)μmol/L。结论丹酚酸B肝脏转运机制可能与OATP密切相关。

Objective To study the pharmacokinetics of salvianolic acid B combined with pitavastatin and the uptaking of salvianolic acid B in rat hepatocytes. Methods SD male rats were randomly divided into two groups （ n = 6 ）. One group was given salvianolic acid B 2.5 g/kg and another group was given salvianolic acid B combined with pitavastatin 0.5 mg/kg. For combined ad- ministration, the salvianolic acid B was first garaged and then pitavastatin. Interval time lasted about 15 min. Blood samples were collected from the orbital vein. The effect of OATP1 B1 substrate of pitavastatin on the pharmacokinetics of salvianolic acid B in rats was examined. Then the primary rat hepatoeytes were separated, the effect of pitavastatin on the hepatocytes uptaking of salvianolic acid B was studied. Results The pharmacokinetic characteristics of salvianolic acid B significantly changed when salvianolic acid B was combined with pitavastatin, the parameters of AUC （0-t）, AUC （0- ∞ ） and Cmax were significantly increased by 54.63%, 69.72%, and 50.56%. Simulatneously, the inhibitory action for uptaking of salvianolic acid B in rat hepatocytes increased gradually with increasing pitavastatin concentration. The IC50 was （5.21 ± 1.68 ） μmol. Condusions The uptaking of salvianolic acid B in hepatocytes may be closely related to OATP.