加替沙星眼凝胶剂兔眼药动学及生物利用度研究

Ocular pharmacokinetics and bioavailability of gatifloxacin ophthalmic gel in rabbits

目的:测定加替沙星眼凝胶兔眼单次和多次给药后不同时间的角膜及房水中的药物浓度,并与加替沙星滴眼液兔比较眼部相对生物利用度.方法:日本大耳白兔随机分为2组,每组40只动物,一组为实验组,单次给予加替沙星眼凝胶(GTX-Gel),另外一组为对照组,分别给予加替沙星滴眼液(GTX-ED).分别于给药后不同时间抽取房水,处死动物后剖取角膜组织,每个时间点均为4只动物8眼.多次给药:日本大耳白兔随机分为2组,一组每眼给予GTX-Gel50mg,作为实验组,另一组每眼给予滴眼液50μL,作为对照组,每4h次,共给药3次,分别于最后一次给药后2,4,12h后抽取房水,处理方法与每个时间点动物数和单次给药相同.药物测定采用反相高效液相色谱法.数据处理采用prizm和DAS2.1.1药动学软件.结果:GTX-Gel组在5～360min各时间点的角膜药物浓度与GTX-ED组比较有统计学差异(P<.05),GTX-Gel组角膜中的AUC0～360是GTX-ED组的4.8倍.GTX-Gel组在5～360min各时间点房水药物浓度与GTX-ED比较有统计学差异(P<0.05).GTX-Gel组房水中的AUC0～360是GTX-ED组的5.5倍.GTX-Gel组多次给药后在,4,12h时角膜中的药物浓度分别是GTX-ED组对应时间点的5.3,2.2和3.0倍,房水中的药物浓度分别是GTX-ED组对应时间点的7.1,2.7,1.5倍.结论:加替沙星眼凝胶单次给药后同滴眼液比较可以显著提高药物在角膜和房水中的药物浓度,增加药物的眼部生物利用度.眼凝胶组多次给药后不同时间点的角膜和房水中的浓度均高于滴眼液组.

AIM： To assay and compare the drug levels in tears, corneas and aqueous humors at different times after single and multiple topical application of 3 g/L gatifloxacin ophthalmic gel （GTX-Gel）, 3 mL/L gatifloxacin ophthalmic solutions （GTX- ED） to rabbits, and evaluate the ocular bioavailability of GTX-Gel. METHODS： Single dose： Japanese white rabbits were randomly divided into 2 groups, each group including 40 rabbits. One of group received 50 mg of GTX-Gel, the other groups received 50 L of GTX-ED, respectively. The two eyes of each rabbit received the same dose of the medications. The aqueous humors were collected at prescheduled time points following topical application of GTX-Gel or GTX-ED, respectively, and the corneas were immediately dissected after euthanized. All samples were stored -60℃. High performance liquid chromatography （HPLC） analysis was used as a detection method. Statistical tests used included an unpaired Student＇s t-test and 3p97 pharmacokinetics software. RESULTS： The drug levels in corneas at 5-360 min time points for GTX-Gel group were significantly higher than GTX-ED group at corresponding times （ P 〈 0.05 ）. The area under the curve（AUC） of the drug concentrations vs times in corneas for GTX-Gel group was 4.8 times as high as GTX-ED group within designed duration. The drug levels in aqueous humors （AH） at 5-360 min for GTX-Gel group were significantly higher than GTX-ED group at corresponding times（ P 〈 0.05 ）. The AUC in AH for GTX-Gel group was 5. 5 times as high as GTX-ED group within designed duration. For the multiple dose, The drug levels in corneas for the GTX-Gel after 2,4 and 12 h last application were 5.3, 2.2 and 3.0 times as high as GTX-ED group at corresponding time points, respectively, and in aqueous humors for GTX-Gel group were 7.1,2.7 and 1.5 times as high as GTX- ED as corresponding time points, respectively. CONCLUSION： Gatifloxacin ophthalmic gel significantly increased the drug levels in corneas and aqueous humors compared to the GTX ophthalmic solutions, thus increased the ocular bioavailability.