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目的:研究与不同剂量丙磺舒(Probenecid)联用对头孢克洛(Cefaclor)药动学的影响及其定量关系,并探讨其可能机制。方法:头孢克洛血、尿药浓度监测:雄性家兔24只,随机分成4组。各组给药剂量如下:Ⅰ组头孢克洛50 mg.kg-1;Ⅱ组头孢克洛50 mg.kg-1联用丙磺舒100 mg.kg-1;Ⅲ组头孢克洛50 mg.kg-1联用丙磺舒250 mg.kg-1;Ⅳ组头孢克洛50 mg.kg-1联用丙磺舒625 mg.kg-1。灌胃给予丙磺舒0.5 h后,再给予头孢克洛,于用药后不同时间取血、尿液样本。HPLC法测定头孢克洛血药及尿药浓度,DAS软件计算药动学参数。血浆蛋白结合率测定:实验分组及剂量同上,给药1 h后取血,以平衡透析法测定头孢克洛血浆蛋白结合率。结果:当丙磺舒联用剂量在0~250 mg.kg-1范围内时,随丙磺舒联用剂量增大,头孢克洛的T1/2ka、Tmax、Cmax、AUC等参数相应增大而CL/F及Vd/F相应降低(P<0.01);但当丙磺舒联用剂量达625 mg.kg-1时,头孢克洛的Cmax降低(P<0.01),AUC、CL/F则稳定于联用丙磺舒250 mg.kg-1时的水平。在本实验剂量范围内,随丙磺舒联用剂量增大,头孢克洛原型尿排泄峰时间逐渐后移,生物半衰期延长及总尿药排泄率显著降低(P<0.01)。丙磺舒联用剂量在0~250mg.kg-1范围内,随丙磺舒联用剂量增大,头孢克洛血浆蛋白结合率显著降低(P<0.01),但当丙磺舒联用剂量达625 mg.kg-1时,头孢克洛血浆蛋白结合率反与头孢克洛单用时水平相当(P>0.05)。结论:联用丙磺舒可以明显改变头孢克洛的药动学过程,使其Vd、CL降低,Cmax增高,AUC增大,生物半衰期延长,总尿药排泄率降低。
OBJECTIVE: To investigate the effects of different doses of Probenecid on the pharmacokinetics of cefaclor and its quantitative relationship, and to explore its possible mechanism. Methods: Cefaclor blood and urine concentration monitoring: 24 male rabbits were randomly divided into 4 groups. The dose of each group were as follows: group Ⅰ cefaclor 50 mg.kg-1; group cefaclor 50 mg.kg-1 with probenecid 100 mg.kg-1; group Ⅲ cefaclor 50 mg. kg-1 with probenecid 250 mg.kg-1; group Ⅳ cefaclor 50 mg.kg-1 probenecid 625 mg.kg-1. Serum probenecid given 0.5 h after cefaclor given again at different times after taking blood, urine samples. HPLC determination of cefaclor blood and urine concentration, DAS software calculated pharmacokinetic parameters. Plasma protein binding rate determination: experimental grouping and the same dose, 1h after administration of blood, to balance dialysis determination of cefaclor plasma protein binding. Results: With the dose of probenecid in the range of 0 ~ 250 mg.kg-1, the parameters of cefaclor such as T1 / 2ka, Tmax, Cmax and AUC increased with the increase of probenecid dose While the values of CL / F and Vd / F decreased (P <0.01). However, when probenecid combined with 625 mg.kg-1, the Cmax of cefaclor decreased (P <0.01) It is stable at the level of probenecid 250 mg.kg-1. In the experimental dose range, cefaclor prototype urinary excretion time gradually shifted with prolonging the dose of probenecid, prolonging the biological half-life and decreasing the total urinary excretion rate (P <0.01). Probenecid combined with doses in the range of 0 ~ 250mg.kg-1, with probenecid combined with the dose increased cefaclor plasma protein binding rate was significantly lower (P <0.01), but probenecid combined with dose At 625 mg.kg-1, cefaclor plasma protein binding rate was comparable to that of cefaclor alone (P> 0.05). Conclusion: Probenecid can significantly change the pharmacokinetics of cefaclor, its Vd, CL decreased, Cmax increased, AUC increased, the biological half-life prolonged, the total urinary excretion rate decreased.