盐酸小檗碱对大鼠体内他克莫司药动学的影响

Effects of Berberine Hydrochloride on the Pharmacokinetics of Tacrolimus in Rats

目的:研究盐酸小檗碱单次、多次给药对大鼠体内他克莫司药动学的影响,为两者联合用药提供参考。方法:将30只大鼠随机分为5组,每组6只,第1组大鼠单次灌胃他克莫司;第2组大鼠每日灌胃他克莫司2次,连续给药1周;第3组大鼠先单次灌胃盐酸小檗碱,5 min后单次灌胃他克莫司;第4组大鼠先每日灌胃他克莫司2次,连续给药1周,第8天时先灌胃盐酸小檗碱5 min后再灌胃他克莫司1次;第5组大鼠每日灌胃盐酸小檗碱2次,每次间隔5 min后相应灌胃他克莫司1次,连续给药8 d。盐酸小檗碱给药剂量均为200 mg/kg,他克莫司给药剂量均为0.945 mg/kg。末次灌胃他克莫司后0、5、15、30 min和1、2、3、4、6、8、12 h,分别从各组大鼠的眼眶后静脉丛取血约0.3 m L,采用液相色谱-串联质谱法(LC-MS/MS)测定大鼠全血中他克莫司的浓度,应用DAS2.0软件进行药动学研究。结果:与第1组比较,第3组大鼠体内的他克莫司药动学参数AUC_(0-12) h、AUC0-∞和MRT0-12 h显著降低(P<0.05),第4组大鼠体内他克莫司所有药动学参数差异均无统计学意义(P>0.05);与第2组比较,第4组大鼠体内他克莫司药动学参数AUC_(0-12) h显著降低、CLz显著升高(P<0.05),第5组大鼠体内他克莫司所有药动学参数差异均无统计学意义(P>0.05)。结论:单次、多次灌胃盐酸小檗碱均对大鼠体内他克莫司的药动学有影响,表现在血药浓度有下降的趋势,需谨慎联用。

OBJECTIVE:To study the effects of berberine hydrochloride on the pharmacokinetics of tacrolimus in rats after single or multiple administration,and to provide reference for clinical combination therapy.METHODS:30 rats were randomly divided into 5 groups,with 6 rats in each group:group one was treated with single administration of tacrolimus;group two was treated with tacrolimus intragastrically,twice a day,for consecutive 1 week;group three was treated with single administration of berberine hydrochloride,5 min later given single administration of tacrolimus;group four was treated with tacrolimus intragastrically,twice a day,for consecutive 1 week,and then given tacrolimus intragastrically once 5 min after intragastric administration of berberine hydrochloride on the 8th day;group five was treated with berberine hydrochloride intragastrically,twice a day,and given tacrolimus intragastrically every 5 min,for consecutive 8 d.The doses of berberine hydrochloride and tacrolimus were 200 mg/kg and 0.945 mg/kg.The blood samples 0.3 mL were collected from posterior orbital venous plexus of rats 0,5,15,30 min and 1,2,3,4,6,8,12 h after last intragastric administration of tacrolimus.The concentration of tacrolimus in rat whole blood was determined by LC-MS/MS.DAS 2.0 software was used for pharmacokinetic study.RESULTS:Compared with group one,the pharmacokinetic parameters AUC0-12 h,AUC0-∞and MRT0-12 h of tacrolimus in rats were decreased significantly in group three(P<0.05),while there was no statistical significance in all pharmacokinetic parameters of tacrolimus in group four(P>0.05).Compared with group two,AUC0-12 h of tacrolimus was decreased significantly while CLz was increased significantly in group four(P<0.05);there was no statistical significance in all pharmacokinetic parameters of tacrolimus in group five(P>0.05).CONCLUSIONS:Single and multiple intragastric administration of berberine hydrochloride has a certain effect on the pharmacokinetics of tacrolimus in rats,it shows that there is a downward trend in blood drug concentration and needs to be used with caution.