P-糖蛋白介导阿托伐他汀与阿昔莫司摄取转运的相互作用及其机制研究

Drug interaction and effect mechanism during the uptake of atorvastatin and acipimox mediated by P-gp

目的:研究阿昔莫司(Aci)的摄取转运机制以及与阿托伐他汀(ATV)联用是否会产生由P-糖蛋白(P-gp)介导摄取转运方面的相互作用。方法:以Caco-2细胞为模型,测定ATV、Aci的表观渗透系数;此外还测定了17名健康受试者C3435T基因多态性以及单次口服ATV 20 mg与Aci 500 mg后不同时间点的血药浓度。结果:在Caco-2细胞模型中,ATV的表观渗透率为2.65;Aci的表观渗透率为1.27,当P-gp抑制剂维拉帕米存在时其表观渗透系数变化不明显。受试者合用ATV与Aci后,ATV的AUC0-t、AUC0-∞在TT、CC基因型组间差异有统计学意义(P<0.05);而Aci的Cmax、AUC0-t、AUC0-∞在不同组间变化相近(P>0.05)。结论:Aci在肠道的摄取转运以被动扩散为主,且不是P-gp的底物,ATV与其联用不会产生由P-gp介导摄取转运方面的相互作用。

AIM： To study the uptake mode of acipimox（ Aci）,explore the uptake of pharmacokinetic interaction and molecular mechanism of atorvastatin（ ATV） coadministrated with Aci on P-glycoprotein. METHODS： By Caco-2 cells monolayer model,the apparent permeability Ratio（ PDR） of ATV and Aci was studied. Furthermore,after 17 healthy subjects were given ATV 20 mg and Aci 500 mg,their C3435 T polymorphism and a series of blood drug concentration were measured. RESULTS： In the Caco-2 cell model,the PDR of ATV was 2. 65; the PDR of acipimox was 1. 27,verapamil of P-gp inhibitor with Aci,the apparent permeability coefficient（ Papp） had no significant change.After ATV coadministrated with Aci by subjects,it had an impact on the absorption characteristics of ATV AUC0- ∞and AUC0- t,there are significantly differences between CC and TT. While there are no significantly differences among the pharmacokinetics parameters（ Cmax,AUC0- ∞,AUC0- t） of Aci with defferent genetype group. CONCLUSION： Aci was not transported by P-glycoprotein which is mainly absorded by simple diffusion in the intestinal tract;it indicated that ATV and Aci together may not exist uptake interaction on P-gp.