盐酸利多卡因眼用凝胶在兔眼房水中药物浓度测定及药动学研究

摘要

Objective: To establish an LC-MS/MS method for the determination of lidocaine in ocular aqueous humor of rabbit and to study the pharmacokinetics of lidocaine hydrochloride ophthalmic gel after a single topical ocular administration. Methods: Seventy-two rabbits were placed in two groups based on the test and reference formulations. Rabbits in each group were instilled with a single 15 μL of lidocaine hydrochloride ophthalmic gel into each eye. Following the sample collection and deproteinization procedures, the lidocaine concentrations in aqueous humor were determined by LC-MS/MS. Letrozole was used as the internal standard and the chromatographic separation was achieved on a Hedara ODS-2 column (5μm, 150 mm×2.1 mm i.d.) with a mobile phase of methanol-0.1% formic acid water solution with 20 mmol·L-1 am-monium acetate(55∶45, V/V). The detection was performed using the electrospray ionization(ESI) operating in the positive ion multiple reaction monitoring(MRM) mode. Results: The method demonstrated good linearity ranged from 2.070 to 10350 ng·mL-1 with r=0.9995. After administration of the test and reference formula-tion to the rabbits, the Cmax values were (10193±4535) ng·mL-1 and (11046±2734) ng·mL-1, respectively, the AUC0-8 values were 7582 ng·h·mL-1 and 8125 ng·h·mL-1, respectively, the t1/2 values were 2.6 h and 1.9 h, respectively, and the Tmax values were both 0.3 h. Conclusion: There was no significant difference of pharmacokinetic characteristics between the two formulations. Lidocaine hydrochloride ophthalmic gel could rapidly achieve a high concentration in aqueous humor after its topical ocular administration to rabbits.%目的：建立兔眼房水中利多卡因的LC-MS/MS检测方法，研究盐酸利多卡因眼用凝胶在兔眼房水中的药动学特征。方法：72只雄性新西兰兔分成Ⅰ和Ⅱ两组，每组36只，Ⅰ和Ⅱ组分别给予盐酸利多卡因眼用凝胶受试制剂和参比制剂，左右眼均滴入15μL，于不同时间点取房水样品，经沉淀蛋白后，采用LC-MS/MS法测定房水中的利多卡因。以来曲唑为内标，采用Hanbon Hedera ODS-2 C18（2.1 mm×150 mm，5μm）色谱柱，流动相为甲醇-20 mmol·L-1醋酸铵水溶液（含0.1%甲酸）（55∶45，v/v），质谱采用气动辅助电喷雾离子化和正离子多重反应监测。结果：利多卡因房水浓度在2.070~10350 ng·mL-1范围内线性关系良好（r=0.9995）。单次给予新西兰兔受试制剂和参比制剂后，房水中利多卡因的Cmax分别为（10193±4535） ng·mL-1和（11046±2734） ng·mL-1，AUC0-8分别为7582 ng·h·mL-1和8125 ng·h·mL-1，t1/2分别为2.6 h和1.9 h，Tmax均为0.3 h。结论：盐酸利多卡因眼用凝胶受试和参比制剂在房水中药动学特征一致，眼部给药后利多卡因可快速穿透角膜到达房水，并在房水中达到较高的浓度。