环孢素A对银杏内酯B大鼠体内药动学的影响  

Effect of cyclosporine A on the pharmacokinetics of ginkgolide B in rats

作　　者：王磊[1] 李宁[1] 韩德恩[1] 孙伟[1] 高子栋[1] 陈西敬[1] 

机构地区：[1]中国药科大学药物代谢与动力学研究中心,江苏南京210009

出　　处：《药学学报》2009年第6期632-639,共8页Acta Pharmaceutica Sinica

基　　金：国家高技术研究发展计划(863计划)资助项目(2007AA02Z171);国家自然科学基金资助项目(30472060)

摘　　要：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。The paper is aimed to investigate the effect of cyclosporine A （CyA） on the pharmacokinetics of ginkgolide B （GB） in rats, and to look for the mechanism of the changes in pharmacokinetic behaviors of GB. GB concentration in plasma, brain homogenate and urine samples of rats was determined by LC-MS. Effects of CyA on plasma levels, brain distributions as well as urinary excretions after intravenous administration of GB were evaluated. CyA coadministrated intravenously at 10 mg·kg^-1 or 20 mg·kg^-1 significantly increased AUC0-360 min （P 〈 0.01） and decreased total CL of GB in rats. While coadministrated CYP3A inhibitor itraconazole （ICZ） has no appreciable effect on the pharrnacokinetic behavior of GB. CyA increased the brain uptake of GB in a dose-dependent manner. The brain distribution of GB was significantly increased at 5 min by different doses of CyA （P 〈 0.001）, while at 20 and 60 min only high dose of CyA could significantly increase the levels of GB in the brain （P 〈 0.01 and P 〈 0.001）. Different P-gp inhibitors CyA or verapamil （VER） or digoxin （DGX） decreased the urinary GB excretion, the urinary excretion of GB in 0-8 h were about 34.8% （P 〈 0.001）, 59.4% （P 〈 0.001） and 79.7% （P 〈 0.05） of the control, separately. No appreciable effect of ICZ was observed on urinary excretion of GB. Coadministration of P-gp inhibitors CyA could significantly increase the plasma level, accelerate the brain distribution and decrease the urinary excretion of GB.

关 键 词：银杏内酯B 环孢素A 药动学 P-糖蛋白 脑分布 肾排泄 

分 类 号：R969[医药卫生—药理学]