目的：对比2%双醋瑞因滴眼液结膜囊多次给药与单次给药在角膜中的药代动力学差异，为临床医师治疗感染性角膜病时多次给药提供实验依据。

方法：以2%双醋瑞因为实验滴眼液，选取健康无眼疾的雄性昆明白小鼠，随机分为多次给药组和单次给药组，双眼结膜囊分别给予双醋瑞因滴眼液。多次给药组间隔2min给药一次，共给药3次； 单次给药组仅给药1次。用高效液相法测定角膜中双醋瑞因的代谢产物(大黄酸)的浓度，多次给药组和单次给药组的时间点均为5、15、30、60、120、180min。将小鼠角膜组织中的药物浓度经药物动力学程序(DAS2.1.1)进行拟合，并计算相关药动学参数。

结果：结膜囊多次给药组和单次给药组各个时间点角膜中均可检测到其活性代谢产物大黄酸； 多次给药组5、15、30、60、120、180min的浓度分别为318.678±40.88、210.02±25.66、188.83±31.74、112.24±11.70、90.28±22.01和57.67±13.71μg/g，单次给药组各时间点浓度分别为145.17±19.29、97.95±10.49、71.18±18.70、39.11±2.44、18.10±2.34和9.08±2.04μg/g。两组小鼠角膜中大黄酸的含量均于给药后5min最高，多次给药组浓度高于单次给药组浓度，差异具有统计学意义(P<0.01)。随时间延长大黄酸的浓度逐渐下降，3h后多次给药组浓度仍高于单次给药组，差异具有统计学意义(P<0.01)。单次给药组半衰期为0.89±0.31h。

结论：结膜囊多次给药与单次给药相比具有药物有效浓度高、维持时间长的优点，双醋瑞因作为一种新的抗菌药物，可以在感染性角膜炎的早期对病程的发展起到抑制作用。多次给药后可以对急性发展期起到较好的治疗效果，而且在夜晚也可维持较高浓度，在保证患者的睡眠休息质量同时又起到了对疾病的治疗作用。

METHODS: Male Kunming mice were randomly divided into the multiple administration group and the single administration group. The multiple administration group were given diacerein eye drop every 2min(3 times in total). The concentrations of the metabolites of diacerein in the cornea were measured by high performance liquid chromatography after given eye drop 5, 15, 30, 60, 120, and 180min. The pharmacokinetic parameters were calculated by pharmacokinetic software(DAS2.1.1).

RESULTS: The metabolites of diacerein, rhein, was detected in the cornea at each time point. The concentration of the metabolite of diacerein in the cornea was 318.678±40.88, 210.02±25.66, 188.83±31.74, 112.24±11.70, 90.28±22.01 and 57.67±13.71μg/g after given eye drop 5, 15, 30, 60, 120, and 180min in the multiple administration group. The concentration in the single administration group was 145.17±19.29, 97.95±10.49, 71.18±18.70, 39.11±2.44, 18.10±2.34 and 9.08±2.04μg/g respectively. The concentration of rhein in the cornea was the highest at 5min after the administration in the two groups. The concentration of the multiple administration group was higher than that in the single administration group at 5, 15, 30, 60, 120, and 180min(P<0.01). The half-life of the drug was 0.89±0.31h in the single administration group.

CONCLUSION: Compared with the single administration, the conjunctival sac multiple administration has the advantages of high drug concentration and long duration. Therefor the conjunctival sac multiple administration is a more effective method to treat acute infectious corneal diseases.