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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。
Objective To investigate the effects of verapamil, a P-gp and CYP3A4 inhibitor, on the pharmacokinetics of amitriptyline and nortriptyline in the brain. Methods Kunming mice were randomly divided into 2 groups: control group (normal saline administration) and verapamil lease (4 mg · kg -1), respectively, once a day, 3 days after administration Rats were injected amitriptyline (15 mg · kg -1) intraperitoneally and were decapitated at 0, 5, 15, 30, 60, 90, 120, 180, 270 and 360 minutes respectively. After the blood was collected, the mice in each group were sacrificed and the brain was quickly removed and stored in liquid nitrogen. The samples were treated by liquid-liquid extraction. The concentration of amitriptyline and its active metabolite nortriptyline in plasma and brain tissues was determined by HPLC-MS. The pharmacokinetic parameters were calculated by plotting the time course of the drug. Results Compared with the control group, the plasma AUC of amitriptyline and nortriptyline in the verapamil group increased by 1.9 and 2.0 times respectively, and increased 3.3 and 3.5 times respectively in the brain. The AUC ratio of amitriptyline and nortriptyline in verapamil group also increased, which were 1.4 and 1.9 times higher than that of the control group respectively. Conclusion Both amitriptyline and nortriptyline may have some P-gp substrate activity, and nortriptyline has stronger affinity with P-gp. Verapamil can increase amitriptyline plasma drug concentration, but also can improve the brain / blood ratio of amitriptyline, which may be related to the inhibition of verapamil on P-gp and CYP.