论文部分内容阅读
研究环孢素A(cyclosporine A,CyA)对大鼠静脉注射中药成分银杏内酯B(ginkgolide B,GB)药动学的影响,并进行作用机制研究。实验建立了测定大鼠血浆、脑组织和尿液中GB浓度的LC-MS方法,研究了CyA对GB在大鼠体内血药浓度、脑分布和肾排泄的影响。结果表明静脉注射CyA(10及20mg·kg-1)可以显著增加GB的AUC0-360min(P<0.01),降低其CL(P<0.001);静脉注射CYP3A抑制剂伊曲康唑(itraconazole,ICZ)则对GB的药动学行为无影响。脑分布结果显示,高、中、低剂量的CyA均可增加GB在脑中的浓度,此作用具有浓度和时间依赖性,在5min时不同剂量的CyA均可显著增加GB在脑中的分布(P<0.001),但在20及60min时仅高剂量CyA组可显著增加GB脑中的浓度(P<0.01及P<0.001)。不同P-gp抑制剂均可减少GB的肾排泄,其中CyA(20mg·kg-1)组、维拉帕米(verapamil,VER)组及地高辛(digoxin,DGX)组GB8h累积排泄百分率仅分别为对照组的34.8%(P<0.001)、59.4%(P<0.001)及79.7%(P<0.05);而ICZ组则无此作用。大鼠静脉给予P-gp抑制剂CyA可以显著提高GB的血药浓度,减少肾脏对GB排泄且能增加GB在脑中的分布。
To study the effect of cyclosporine A (CyA) on the pharmacokinetics of ginkgolide B (GB) injected intravenously in rats and to study its mechanism. The LC-MS method was established to determine the concentration of GB in rat plasma, brain tissue and urine, and the effect of CyA on GB concentration, brain distribution and renal excretion in rats was studied. The results showed that intravenous injection of CyA (10 and 20 mg · kg-1) significantly increased GB AUC0-360min (P <0.01) and decreased CL (P <0.001). Intravenous injection of CYP3A inhibitor itraconazole ) Has no effect on the pharmacokinetic behavior of GB. Brain distribution results showed that high, medium and low doses of CyA can increase the concentration of GB in the brain, the role of concentration and time-dependent, at different doses of CyA 5min significantly increased the distribution of GB in the brain ( P <0.001). However, high dose CyA alone significantly increased the concentration of GB in the brain at 20 and 60 min (P <0.01 and P <0.001). Different P-gp inhibitors could reduce renal excretion of GB, and the cumulative excretion rate of GB8h in groups of CyA (20mg · kg-1), verapamil (VER) and digoxin (DGX) Which were 34.8% (P <0.001), 59.4% (P <0.001) and 79.7% (P <0.05) respectively in the control group, but not in the ICZ group. Intravenous administration of P-gp inhibitor CyA in rats can significantly increase GB blood concentration, reduce renal excretion of GB and can increase the distribution of GB in the brain.