摘要
目的：应用液相色谱-串联质谱法（LC/MS/MS）测定比格犬给药后血浆中氨苄西林和丙磺舒的血药浓度，绘制血药浓度-时间变化曲线，根据曲线计算主要药动学参数，并进行方差分析。
方法：本试验采用双周期随机交叉试验设计，分别对6只比格犬静脉注射给予低、中、高三个剂量水平的氨苄西林钠（对照组）和氨苄西林钠/丙磺舒钠（试验组）的药动学行为进行考察。采用液相色谱-质谱-质谱联用法(LC/MS/MS) ，分别测定了给药后不同时刻比格犬血浆中氨苄西林钠和氨苄西林钠/丙磺舒钠浓度，绘制了血药浓度-时间曲线。根据血药浓度-时间数据，采用梯形法计算AUC ；以半对数作图法，由消除相末端后四个浓度点计算t1/2，求出主要药动学参数并对其进行方差分析。
结果与结论：6只比格犬静脉给予氨苄西林钠（对照组），剂量分别为40, 80和160 mg(kg-1时，血浆中氨苄西林的t1/2分别为0.70±0.10 ，0.92±0.07和 1.49±0.13 h；AUC0-t分别为129.8±28.04，142.8±24.92和233.7±48.71 (g(h(ml-1；AUC0-(分别为130.1±28.07，143.0±24.94和234.0±48.78 (g(h(ml-1。
6只比格犬静脉给予氨苄西林钠/丙磺舒钠（试验组），剂量分别为40/13.5, 80/27和160/54 mg(kg-1时，血浆中氨苄西林的t1/2分别为0.98±0.09 ，1.15±0.11和 1.75±0.21 h；AUC0-t分别为160.2±16.27，171.8±41.79和275.5±79.55 (g(h(ml-1；AUC0-(分别为160.5±16.29，172.1±41.79和276.1±79.77 (g(h(ml-1。血浆中丙磺舒的t1/2分别为10.63±3.92 ，13.78±5.06和 9.91±2.93 h；AUC0-t分别为709.4±170.5，1832.6±650.8和2632.8±980.2 (g(h(ml-1；AUC0-(分别为756.3±216.2，2250.6±994.9和2773.2±1101.9 (g(h(ml-1。
将对照组（氨苄西林钠）和试验组（氨苄西林钠/丙磺舒钠）的主要药物动力学参数进行方差分析（AUC0-t和AUC0-(需进行对数转换），结果表明：对照组和试验组之间（两制剂间）氨苄西林的药物动力学参数t1/2 、AUC0-t和AUC0-(都有显著性差异（P<0.05）。与对照组相比，试验组氨苄西林的消除半衰期t1/2有所延长，AUC0-t和AUC0-(有所提高，可以认为丙磺舒确实具有延缓氨苄西林消除的作用。
Aim: To develop a LC/MS/MS method for determination of ampicillin and probenecid in beegles dogs’ plasma. Use this method, we could obtain the concentration-time profiles of the two drugs. Furthermore, after calculated the PK parameters, the main parameters obtained were analyzed by ANOVA.
Method: To study the different behaviors on pharmacokinetics of ampicillin (reference) and ampicillin / probenecid (test) after administrated to 6 beegles dogs designed by two period cross-over at high, middle and low dose level, respectively. The concentration was determined by LC/MS/MS and a concentration-time profiles could be obtained. The values of AUC were calculated with trapezoid method, t1/2 was calculated according to the last four points in the elimination phase.
Results and conclusion: The values of t1/2 of ampicillin (in the reference group) in 6 beegles dogs are 0.70±0.10, 0.92±0.07 and 1.49±0.13 h at the intravenous dosage of 40, 80 and 160 mg(kg-1 respectively. And the values of AUC0-t were 129.8±28.04，142.8±24.92 and 233.7±48.71 (g(h(ml-1, the values of AUC0-( were 130.1±28.07，143.0±24.94 and 234.0±48.78 (g(h(ml-1, respectively. However, the corresponding values of ampicillin (in the test group) were as follows: t1/2, 0.98±0.09, 1.15±0.11and 1.75±0.21 h; AUC0-t, 160.2±16.27, 171.8±41.79 and 275.5±79.55 (g(h(ml-1; AUC0-(, 160.5±16.29, 172.1±41.79 and 276.1±79.77 (g(h(ml-1。The values of t1/2 of probenecid in the test group were 10.63±3.92 , 13.78±5.06 and 9.91±2.93 h; The values of AUC0-t were 709.4±170.5, 1832.6±650.8 and 2632.8±980.2 (g(h(ml-1; And the values of AUC0-( were 756.3±216.2, 2250.6±994.9 and 2773.2±1101.9 (g(h(ml-1, respectively.
The main parameters including t1/2 、AUC0-t and AUC0-( were analyzed with ANOVA(AUC0-t and AUC0-( were transferred by logarithm first). The results showed that there were significant differences in these three parameters in the two groups. Contrary to the reference group, the values of t1/2 were longer and the values of AUC0-t and AUC0-( were higher in the test group. All of these indicated that probenecid could reduce the elimination rate of ampicillin in beegles dog after intravenously dosed.
引文
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