盐酸小檗碱对大鼠体内咪达唑仑及其代谢产物药动学的影响  

Effects of Berberine on In Vivo Pharmacokinetics of Midazolam and Its Metabolite in Rats

作　　者：常伟宇[1,2] 辛华雯[2] 唐霞[2] 欧阳萌[2] 钟建勋[2] 

机构地区：[1]南方医科大学药学院药理系,广州510515 [2]广州军区武汉总医院临床药理科,武汉430070

出　　处：《医药导报》2016年第4期331-336,共6页Herald of Medicine

摘　　要：目的观察盐酸小檗碱(BER)对细胞色素P450酶3A(CYP3A)底物咪达唑仑(MDZ)在大鼠体内代谢的影响。方法给予大鼠不同剂量BER(50,100,200 mg·kg-1)、酮康唑(75 mg·kg-1),连续灌胃10 d后,采用单次十二指肠给予MDZ(20 mg·kg-1)以及腹股沟动脉插管采血,以CYP3A抑制药(酮康唑)为阳性对照,采用高效液相色谱(HPLC)法测定大鼠血浆MDZ及其代谢物1'-羟基咪达唑仑(1'-OH-MDZ)浓度,研究MDZ在大鼠体内的代谢。结果大鼠给予不同药物后,BER(50,100,200 mg·kg-1)和酮康唑(75 mg·kg-1)均能够显著升高MDZ的AUC(0-t)、AUMC(0-t)、Cmax(P<0.05),且呈剂量依赖性,并且能够减慢其清除率(CLz),减小MDZ在体内的表观分布容积(Vz)(P<0.05),但是对MDZ的半衰期(t1/2z)和血药浓度达峰时间(tmax)无显著性影响。BER(100,200 mg·kg-1)和酮康唑(75 mg·kg-1)能够显著降低1'-OH-MDZ的AUC(0-t)、AUMC(0-t)、Cmax(P<0.05),呈剂量依赖性,能够加快1'-OH-MDZ在体内的CLz、tmax,并增大其Vz(P<0.05),对t1/2z无显著性影响,AUC(1'-OH-MDZ)/AUC(MDZ)的比值随着BER剂量增加而减少。结论 BER抑制MDZ代谢呈现剂量依赖性显著增强,该抑制作用很有可能是BER抑制CYP3A酶活性。Objective To examine the effect of berberine hydrochloride（ BER） on the pharmacokinetic profiles of midazolam,a substrate of CYP3 A,in rats. Methods The rats were intragastrically given different doses of BER（ 50,100,200 mg·kg^-1） or ketoconazole（ 75 mg·kg^-1） for 10 days.Single-pass duodenum perfusion of 20 mg·kg^-1DZ was performed and the inguinal artery was cannulated for blood sampling.Plasma concentrations of MDZ and 1＇-OH-MDZ were analyzed by high performance liquid chromatography（ HPLC） with the CYP3 A inhibitor ketoconazole serving as positive control. Results BER（ 50,100,200 mg·kg^-1） and ketoconazole（ 75 mg·kg^-1） could significantly increase the AUC（ 0-t）,AUMC（ 0-t）and Cmaxof MDZ in a dose-dependent manner（ P〈0.05）,and reduce the clearance rate（ CLz） of MDA and its apparent volume of distribution in the body（ Vz）（ P〈0.05）. But they failed to dramatically affect the half-life（ t1 / 2z） and the peak time（ tmax） of MDZ.Additionally,BER（ 100,200 mg · kg-1） and ketoconazole（ 75 mg·kg^-1 could significantly dose-dependently decrease the AUC（ 0-t）,AUMC（ 0-t）and Cmaxof 1＇-OH-MDZ,and profoundly increase the CLz,tmaxand Vzof 1＇-OH-MDZ（ P〈0.05）,but they had no remarkable influences on the t1 / 2z.The ratio of AUC（ 1＇-OH-MDZ）/ AUC（ MDZ）was decreased with the increase of BER concentration.Conclusion BER can inhibit the in vivo metabolism of MDZ in a dose-dependant manner,which is associated with the suppression of the activity of CYP3 A.

关 键 词：小檗碱 盐酸 咪达唑仑 细胞色素P450酶3A 药动学 相互作用 药物 

分 类 号：R286[医药卫生—中药学] R965[医药卫生—中医学]