五味子甲素对P-糖蛋白抑制作用的体内外研究

摘要

目的 研究五味子甲素对P-糖蛋白(P-gp)的影响.方法 选用Caco-2细胞模型体外研究P-gp对不同浓度五味子甲素(20,40,80 μg· mL-1)转运的影响,同时测定五味子甲素(20 ～ 160 μg· mL-)对P-gp底物——罗丹明123和环孢素A表观渗透系数(Papp)的影响.40只雄性SD大鼠随机分为5组:空白对照组、维拉帕米组、五味子甲素小、中、大剂量组.五味子甲素小、中、大剂量组每日分别灌胃给予五味子甲素8,16,32 mg· kg-1,维拉帕米组给予维拉帕米4mg·kg-1,空白对照组给予等体积纯化水.连续给药3d,每日1次.最后一次给药30 min后立即灌胃给予5 mg·kg-1的罗丹明123,测定罗丹明123药动学特征,体内评价五味子甲素对P-gp的效应.结果 P-gp对20,40,80 μg· mL-1五味子甲素的双向转运无选择差异;五味子甲素(20 ～ 160 μg· mL-1)可显著抑制罗丹明123和环孢素A在Caco-2细胞模型中基底面→顶面(BL→AP)定向转运速率(P＜0.05),且呈剂量相关性;五味子甲素(8～32 mg·kg-1)可剂量依赖性降低大鼠血浆罗丹明123峰浓度(Cmax)和血浆浓度-时间曲线下的面积(AUC0-t).结论 五味子甲素在体内外均可显著抑制P-gp,但不是P-gp底物.%Objective To investigate the influence of deoxyschizandrin (Deo) on P-glycoprotein (P-gp).Methods The effect of P-gp on Deo (20,40,80 μg·mL-1) was studied in the Caco-2 cell model in vitro,and the apparent permeability coefficient (Papp) of Deo (20-160 μg·mL-1) on a P-gp substrate,rhodamine123 or cyclosporine A,was calculated.Healthy male Sprague-Dawley rats were randomly divided into five groups:blank control group,verapamil group,low-,medium-and high-dose Deo group (8 rats in each group).Rats in the low-,medium-and high-dose Deo group were intragastrically administered once daily with Deo at 8,16 and 32 mg·kg-1 for 3 consecutive days,while rats similarly received gavagewith verapamil (4 mg·kg-1) in the verapamil group and equal volume of purified water in the blank control group.Thirty minutes after the rats were treated with their respective drugs,rhodamine123 (5 mg· kg-1) was orally administrated.Then the pharmacokinetic profiles of rhodamine 123 were analyzed to evaluate the inhibitory ability of Deo on P-gp in vivo.Results The bidirectional transport rates of Deo (20,40,80 μg·mL-1) were similar,with non-selectivity.Deo (20-160 pg·mL-1)significantly inhibited the basolateral→apical(BL→AP) directional transports of rhodamine 123 and cyclosporine A in Caco-2 cell model (P ＜ 0.05) in a concentration-dependent manner.And Deo (8-32 mg· kg-1) also dose-dependently decreased the peak concentrations (Cm.) and the area under the plasma concentration-time curve (AUC0-t) of Rho123.Conclusion Deo can inhibit P-gp in vitro and in vivo,but it is not a P-gp substrate.