维拉帕米对小鼠阿米替林和去甲替林脑内药动学的影响

目的 研究P-gp和CYP3A4抑制剂维拉帕米对阿米替林和去甲替林脑内药动学的影响。方法 昆明种小鼠随机分为2组，分别给于对照组(生理盐水给药)和维拉帕米租(4 mg·kg^-1)，早晚各给药1次，给药3 d后小鼠腹腔注射阿米替林(15 mg·kg^-1)，并分别于0，5，15，30，60，90，120，180，270，360 min断头取血。采血完毕后将各组小鼠处死，快速取出大脑，置液氮中保存。用液液萃取的方法处理样品，采用HPLC-MS测定血浆和脑组织中阿米替林及其活性代谢物去甲替林的浓度，绘制药时曲线，求算药动学参数。结果 相较于对照组，维拉帕米组的阿米替林及去甲替林血浆AUC分别升高1.9，2.0倍；脑内分别升高了3.3，3.5倍。维拉帕米组阿米替林及去甲替林脑/血AUC比值也有所升高，与对照组相比分别提高了1.4，1.9倍。结论 阿米替林及去甲替林可能均具有一定P-gp底物活性，且去甲替林与P-gp亲和力更强。维拉帕米能增加阿米替林血浆药物浓度的同时，也可以提高阿米替林脑/血比值，这可能与维拉帕米对P-gp及CYP的抑制有关。

Effect of Verapamil on the Brain Pharmacokinetics of Amitriptyline and Nortriptyline in Mice

OBJECTIVE To study the influence of verapamil on the brain pharmacokinetics of amitriptyline(AMI) and nortriptyline(NOR) in mice. METHODS Kunming mice were equally divided into two groups by completely random design. Mice in each group were injected intraperitoneally with saline or verapamil(4 mg·kg^-1) twice a day. After 3 days, blood samples were collected at 5, 15, 30, 60, 90, 120, 180, 270, 360 min after AMI injected. Brain samples were removed after blood collecting and stored in liquid nitrogen. The whole AMI and NOR concentration in blood and brain samples were determined by HPLC-MS, the WinNonlin6.1 software was used to calculate the pharmacokinetics parameters. RESULTS Compared with the control group, the AUC of amitriptyine and NOR in verapamil group were increased by 1.9, 2.0 fold in plasma and 3.3, 3.5 fold in brain, respectively; the brain-to-plasma concentration ratio of amitriptyine and NOR were also increased by 1.4, 1.9 fold in verapamil group. CONCLUSION It is very likely that AMI and NOR are both P-gp substrates. Compared with AMI, NOR may have a better affinity to P-gp. Verapamil is a good inhibitor of both CYP and P-gp, it can also lead to a great enhancement of the concentration of AMI and increase the brain-to-plasma concentration ratio of AMI significantly.