Madhu C, Rix P J, Shackleton M J, Nguyen T G, Tang-Liu D D
Department of Pharmacokinetics, Allergan, Inc., Irvine, CA 92713-9534, USA.
J Pharm Sci. 1996 Apr;85(4):415-8. doi: 10.1021/js9504189.
This study was designed to examine the effect of benzalkonium chloride/ethylenediaminetetraacetic acid (BAK/EDTA) on the ocular bioavailability (Focular) of ketorolac tromethamine after ocular instillation to normal and de-epithelialized corneas of rabbits both in vitro and in vivo. The in vitro Focular of the formulations was measured in flow-through perfusion chambers. For in vivo studies, a 35 microL dose of 0.5% ketorolac tromethamine with or without BAK/EDTA was instilled into rabbit eyes with intact or de-epithelialized corneas. At 0.5, 1, 2, 4, 6, and 8 h postdose, rabbits were euthanized, and the corneas and aqueous humor were collected from both eyes. The ketorolac concentrations from both in vivo and in vitro samples were quantified by reversed-phase high-performance liquid chromatography. The in vitro study results indicated that BAK/EDTA statistically significantly increased the Focular of ketorolac through de-epithelialized corneas but not through intact corneas. The in vivo study results showed that BAK/EDTA had no effect on the Focular of ketorolac in rabbits with intact corneas, based on the values of the area under the aqueous humor concentration versus time curves (AUC0-6h) of ketorolac. As expected, de-epithelialization of the corneas produced a faster and greater ocular absorption of ketorolac as evidenced by the smaller Tmax and larger AUC values compared to those for the intact corneas in vivo. However, BAK/EDTA decreased the ocular absorption of ketorolac in rabbits with de-epithelialized corneas. The half-lives (t 1/2) of ketorolac in corneal tissue and aqueous humor were longer in rabbits with intact corneas than those in rabbits with de-epithelialized corneas. In conclusion, the in vivo Focular of ketorolac was not altered by BAK/EDTA in rabbits with intact corneas, but it was decreased by BAK/EDTA in rabbits with de-epithelialized corneas. Therefore, the formulation with ketorolac alone may be better as a post-operative ocular analgesic.
本研究旨在考察苯扎氯铵/乙二胺四乙酸（BAK/EDTA）对兔正常角膜和去上皮角膜滴眼后酮咯酸氨丁三醇眼内生物利用度（Focular）的影响，分别进行体外和体内实验。通过流通灌注室测定制剂的体外Focular。对于体内研究，将35微升含或不含BAK/EDTA的0.5%酮咯酸氨丁三醇剂量滴入角膜完整或去上皮的兔眼。给药后0.5、1、2、4、6和8小时，对兔实施安乐死，收集双眼的角膜和房水。通过反相高效液相色谱法定量体内和体外样品中的酮咯酸浓度。体外研究结果表明，BAK/EDTA通过去上皮角膜可使酮咯酸的Focular有统计学意义的显著增加，但通过完整角膜则无此作用。体内研究结果显示，基于酮咯酸房水浓度-时间曲线下面积（AUC0-6h）值，BAK/EDTA对角膜完整兔眼的酮咯酸Focular无影响。正如预期，与体内角膜完整的兔相比，角膜去上皮使酮咯酸的眼内吸收更快且更多，表现为Tmax更小，AUC值更大。然而，BAK/EDTA降低了角膜去上皮兔眼的酮咯酸眼内吸收。角膜完整兔的角膜组织和房水中酮咯酸的半衰期（t 1/2）长于角膜去上皮兔。总之，BAK/EDTA对角膜完整兔眼的酮咯酸体内Focular无改变，但对角膜去上皮兔眼的酮咯酸体内Focular有降低作用。因此，单独使用酮咯酸的制剂作为术后眼用镇痛药可能更好。
