肠道菌群变化对替格瑞洛在大鼠体内药代动力学的影响

Effect of the intestinal flora on the pharmacokinetics of ticagrelor in rats

目的探究肠道菌群变化对替格瑞洛在大鼠体内药代动力学的影响。方法将45只SD大鼠随机分为对照组、实验A组和实验B组,分别灌胃予以等量蒸馏水、双歧杆菌乳杆菌三联活菌片0.8 g·kg^(-1)、阿莫西林克拉维酸钾片125 mg·kg^(-1),连续7 d。第8天,3组大鼠均予以替格瑞洛18 mg·kg^(-1),并于给药前和给药后0.08,0.25,0.50,1,1.5,2,3,4,6,8,12,24 h眼内眦取血,用LC-MS/MS法测定血药浓度。用DAS 2.1.1软件拟合药代动力学参数,用SPSS21.0软件对药代动力学参数进行统计分析。结果实验A组、实验B组和对照组替格瑞洛的主要药代动力学参数如下:AUC_(0-t)分别为(6336.24±1840.46),(4444.05±1033.43),(4469.32±928.47)ng·mL^(-1)·h;AUC_(0-∞)分别为(6841.98±1975.95),(4656.66±1083.78),(4736.47±897.42)ng·mL^(-1)·h^(-1);C_(max)分别为(858.65±275.98),(648.81±215.59),(617.49±168.95)ng·mL^(-1);t_(1/2)分别为(6.40±2.18),(5.25±1.39),(5.68±2.08)h;t_(max)分别为(0.88±0.23),(0.90±0.21),(1.30±0.59)h;清除率分别为(2.82±0.72),(4.07±0.99),(3.95±0.91)L·h^(-1)·kg^(-1);表观分布容积分别为(26.07±12.00),(31.45±14.65),(32.95±14.17)L·kg^(-1)。实验A组与对照组的AUC_(0-t)、AUC_(0-∞)、C_(max)、t_(max)和清除率比较差异均有统计学意义(P<0.05);实验B组与对照组的药代动力学参数比较,差异均无统计学意义(P>0.05)。结论肠道益生菌增加会使替格瑞洛的C_(max)增加,AUC_(0-t)和AUC_(0-∞)增大清除率下降。

Objective To study the effect of intestinal flora on the pharmacokinetics of ticagrelor in rats.Methods A total of 45 SD rats were randomly divided into control group,test A group and test B group.Rats of test groups were orally given live combined bifidobacterium and lactobacillus tablets for 7 days,respectively;rats of control group were given the same volume distilled water.On day 8,ticagrelor was orally administered to all rats.Blood samples were obtained at 0.08,0.25,0.50,1,1.5,2,3,4,6,8,12,24 h after ticagrelor administration.The plasma concentration of ticagrelor was determined by LC-MS/MS.The pharmacokinetic parameters were determined by DAS 2.1.1 software and the statistic analysis was processed with SPSS 21.0 software.Results The pharmacokinetic parameters of ticagrelor in the test A group,test B group and control group were as follows：AUC（0-t） were（6336.24 ± 1840.46）,（4444.05 ± 1033.43） and（4469.32 ±928.47） ng · mL^-1 · h^-1;AUC（0-∞） were（6841.98 ± 1975.95）,（4656.66 ± 1083.78） and（4736.47 ± 897.42） ng · mL^-1 · h;C（max） were（858.65 ±275.98）,648.81 ±215.59） and（617.49 ± 168.95） ng · mL^-1;t（1/2） were（6.40 ±2.18）,（5.25 ±1.39） and（5.68 ±2.08） h;t（max） were（0.88 ± 0.23）,（0.90 ±0.21） and（1.30 ±0.59） h;clearance（CL） were（2.82 ±0.72）,（4.07 ±0.99） and（3.95 ±0.91） L · h（-1）· kg^-1;apparent volume of distribution（V）were（26.07 ± 12.00）,（31.45 ± 14.65） and（32.95 ± 14.17） L · kg^-1.There were significant differences in AUC（0-t）,AUC（0-∞）,C（max）,t（max） and CL between test A group and control group（P〈0.05）.On the contrary,no significant differences were observed on the pharmacokinetic parameters between test B group and control group.Conclusion Increased intestinal probiotics can increase the AUC（0-t）,AUC（0-∞）,and C（max） of ticagrelor,while decrease the CL of ticagrelor.