维拉帕米和丙磺舒对CPU-86017血脑通透及其在心肾中分布的影响  

Effect of verapamil and probenecid on the permeability of CPU-86017 through the blood-brain barrier and the disposition in heart and kidney tissues

作　　者：杜荣辉[1] 林生[1] 戴德哉[1] 管立[1] 

机构地区：[1]中国药科大学药理研究室,南京210009

出　　处：《中国新药杂志》2005年第5期551-555,共5页Chinese Journal of New Drugs

基　　金：国家自然科学基金(30230170)

摘　　要：目的:探讨P-糖蛋白(P-gp)抑制剂维拉帕米(verapamil,Ver)和有机离子转运抑制剂丙磺舒(probenecid,Prob)的干预对对氯苄基四氢小檗碱(CPU-86017)血脑屏障双相通透性、及其在心脏和肾脏中分布的影响。方法:小鼠随机分为3组:Ver组、Prob组及对照组,Ver组和Prob组分别腹腔注射Ver 2mg·kg^(-1)和Prob 1mg·kg^(-1),给药5d,对照组给予生理氯化钠溶液,末次给药24h后,各组再分别静脉(iv)或脑室(icv)给予CPU-860173mg·kg^(-1),HPLC检测给药后1,5,10,20及30min时血清、脑、心和肾中CPU-86017浓度。结果:小鼠iv CPU-86017后,Ver组和Prob组脑内各时间点的药物浓度(从血到脑的通透性)均明显提高(P<0.05);icv CPU-86017后,Ver组血清中药物浓度(脑到血的通透性)显著低于对照组(P<0.05),Prob组与对照组相比差异无显著性(P>0.05)。两种给药途径中,CPU-86017在Ver组心脏及肾脏中的浓度均显著增加,在Prob组肾脏中的浓度有所减少。结论:①P-gp抑制剂维拉帕米和有机离子转运抑制剂丙磺舒均能增加CPU-86017从血到脑的通透。②维拉帕米能增强CPU-86017在心脏和肾脏中的分布,丙磺舒对CPU-86017在心脏中的分布无显著影响,但降低了CPU-86017在肾脏中的分布:③与CPU-86017协同给予P-gp抑制剂维拉帕米能增加CPU-86017在中枢神经系统和靶器官的浓度。Objective: To investigate the effects of verapamil (Ver, a P-glycoprotein inhibitor) and probenecid (Prob, an organic anion transport blocker) on the permeability of p-chloro-benzyl-tetrahydro-berberine(CPU-86017) through the blood-brain barrier and the disposition of CPU-86017 in heart and kidney tissues. Methods: Mice were randomly ip received either Ver (2mg?kg^(-1)), Prob (1mg·kg^(-1)) or normal saline (control) for 5 days, and subsequently iv or icv administered with CPU-86017 (3mg·kg^(-1)), respectively. The CPU-86017 concentrations in the serum, brain, heart and kidney tissues were measured in 1,5,10,20 and 30 min after iv or icv administration by HPLC. Results:The cerebral CPU-86071 concentrations in both Ver and Prob group were significantly increased at all of measured timepoints after iv administration, compared with the control group (P<0.05).The serum CPU-86017 concentration in the Ver group was significantly lower than the one in the control group (P<0.05) after icv administration. The CPU-86017 level in heart and kidney tissues was higher for the Ver-administered mice, but lower in the kidney tissues for the Prob-administered mice, compared with the ones of the control group after the iv and icv administration. No statistical differences of the serum CPU-86071 concentrations were foun(?) between the Prob group and the control group (P> 0.05) after icv administration. Conclusion: Both verapamil and probenecid may coordinate the trans port of more CPU-86017 from peripheral blood vessels to the brain over the BBB. Verapamil could involve in the enhancement of the CPU-86017 concentration in heart and kidney tissues. Probenecid showed insignificant effects in the CPU-86017 distribution in heart tissues, but tapered off the CPU-86017 concentration in kidney tissues. Co-administration of verapamil with CPU-86017 could escalate the CPU-86017 concentration in central nervous system and relevant targeted organs.

关 键 词：对氯苄基四氢小檗碱(CPU-86017) P-糖蛋白 有机离子转运 维拉帕米 丙磺舒 血脑通透性 

分 类 号：R972.2[医药卫生—药品] R965.1[医药卫生—药学]