Systemic absortion and adverse effects of topical ocular use of ketorolac tromethamine and sodium diclofenac in New Zealand rabbits for 90 days

ABSTRACT The effect of the systemic absorption of 0.1% diclofenac sodium (DS) eyedrop was compared to that of 0.5% ketorolac tromethamine (KT) in female New Zealand white rabbits treated on both eyes three times a day for 90 days. The rabbits were divided in three groups of six animals (n= 18): KT group, DS group, and control (Co) group, in which saline (0.9% NaCl) solution was instilled. Water and food consumption were measured daily, clinical examination was performed weekly, and blood samples were collected every 30 days for laboratory examination. The plasma was analyzed for the presence of KT and DS by solid-phase extraction (SPE) associated with mass spectrometry (MS). Systemic absorption of these drugs was confirmed by SPE-MS, allowing their separation and identification in the plasma. At the end of the treatment, the animals were euthanized and necropsied, and no macroscopic or microscopic changes were found. This observation confirmed the laboratory results, which were within normal reference standards for the species. According to the results obtained, it can be concluded that treatment with eyedrops containing KT and DS for 90 days in healthy rabbits does not cause adverse systemic effects.

【摘要】本研究以雌性新西兰白兔为实验对象，每日双眼给药3次、连续给药90天，比较0.1%双氯芬酸钠（diclofenac sodium, DS）滴眼剂与0.5%酮咯酸氨丁三醇（ketorolac tromethamine, KT）滴眼剂的全身吸收效应。实验将18只白兔分为3组，每组6只（n=18）：KT组、DS组及对照组（Co组），对照组给予生理盐水（0.9%氯化钠溶液）滴眼。每日记录实验兔的饮水量与进食量，每周开展临床检查，每30天采集血液样本用于实验室检测。采用固相萃取（solid-phase extraction, SPE）联合质谱（mass spectrometry, MS）分析血浆中KT与DS的存在情况，该方法可实现两种药物在血浆中的分离与鉴定，证实了药物的全身性吸收。给药周期结束后，对所有实验兔实施安乐死并进行尸检，未观察到大体或微观形态学异常改变；该尸检结果与实验室检测结果一致，所有检测指标均处于该物种的正常参考范围内。基于本研究结果可得出结论：健康家兔连续90天使用含KT或DS的滴眼剂，未引发全身性不良反应。