利伐沙班对那格列奈在大鼠体内药代动力学的影响

Effects of rivaroxaban on the pharmacokinetics of nateglinide in rats

目的研究利伐沙班对那格列奈在大鼠体内药代动力学的影响。方法按照体重将大鼠随机分为2组:实验组和对照组,每组18只。实验组灌胃利伐沙班1. 33 mg·kg-1,对照组灌胃等量的空白混悬液,每天1次,连续5 d。第5天灌胃30 min后,2组均灌胃那格列奈16 mg·kg-1,并于灌胃前和后10,20,30,45 min和1,1. 5,2,3,4,6,8 h眼内眦取血,用超高效液相色谱(UPLC)法测定血药浓度。流动相为乙腈-10 mmol·L-1磷酸二氢钾缓冲盐(p H=4. 25;41∶59),波长210 nm;内标为格列齐特。用DAS2. 1. 1软件计算药代动力学参数。结果实验组与对照组主要药代动力学参数如下:AUC0-t分别为(7. 98±3. 05),(5. 87±2. 32) mg·h·L-1;AUC0-∞分别为(8. 36±3. 33),(6. 11±2. 48)mg·h·L-1;t1/2分别为(1. 80±0. 57),(1. 72±0. 51) h;tmax分别为(0. 56±0. 25),(0. 67±0. 29) h;CL分别为(2. 29±1. 07),(3. 17±1. 69)L·h-1·kg-1;V分别为(5. 95±3. 31),(7. 32±3. 05) L;Cmax分别为(4. 69±1. 49),(3. 34±1. 23) mg·mL-1。实验组的t1/2、tmax和V与对照组相比,差异均无统计学意义(均P> 0. 05);实验组与对照组比较,AUC0-t、AUC0-∞和Cmax明显增加,CL明显减小,差异均有显统计学意义(均P <0. 05)。结论利伐沙班可增加大鼠体内那格列奈的生物利用度,并使那格列奈的消除速度减慢。

Objective To investigate the effect of rivaroxaban on the pharmacokinetics of nateglinide in rats.Methods Wistar rats were randomly divided into 2 groups with 18 rats in each group.The rats in test group were orally administered with rivaroxaban 1.33 mg·kg-1 for consective five days,while the rats in control group were administered orally with the same volume of 0.3%CMC-Na.All rats in two groups were given nateglinide 16 mg·kg-1 after the last administration of rivaroxaban or CMC-Na.The plasma concentration of nateglinide were determined by ultra performance liquid chromatography(UPLC)at 0,10,20,30,45 min and 1,1.5,2,3,4,6,8 h after administration.The mobile phase consisted of acetonitrile-10 mmol·L-1 potassium dihydrogen phosphate buffer salt(adjust to pH=4.25 with phosphoric acid;41∶59).The detection wavelength was set at 210 nm.Glidazide was selected as the internal standard.The pharmacokinetic parameters were calculated by DAS 2.1.1.Results The pharmacokinetic parameters of nateglinide in test group and control group were as follows:AUC0-twere(7.98±3.05)and(5.87±2.32)mg·h·L-1;AUC0-∞were(8.36±3.33)and(6.11±2.48)mg·h·L-1;t1/2 were(1.80±0.57)and(1.72±0.51)h;tmaxwas(0.56±0.25)and(0.67±0.29)h;CL were(2.29±1.07)and(3.17±1.69)L·h-1·kg-1;V were(5.95±3.31)and(7.32±3.05)L;Cmaxwere(4.69±1.49)and(3.34±1.23)μg·m L-1,respectively.There was no significant difference in t1/2,tmaxand V,while there were significant differences in AUC0-t,AUC0-∞,CL and Cmax(all P<0.05).Conclusion Rivaroxaban can significantly increase the bioavailability and slow down the clearance of nateglinide in rats.