Bito L Z, Baroody R A
Exp Eye Res. 1987 Feb;44(2):217-26. doi: 10.1016/s0014-4835(87)80006-4.
These experiments were undertaken to determine whether the increased ocular hypotensive potency of topically applied prostaglandin (PG) PGF2 alpha esters, as compared with that of PGF2 alpha free acid, can be accounted for by increased penetration of the eicosanoid moiety of the esterified PG into the eye. One hour after the topical application of [3H]PGF2 alpha-1-methyl ester (ME) in peanut oil, the 3H activities in the cornea, aqueous humor, and ciliary body of the rabbit eye were 32-, 22-, and 8-fold higher, respectively, than they were following the topical application of [3H]PGF2 alpha free acid. 3H activity during the first 3 hr declined rapidly in the cornea and more slowly in the aqueous humor, but remained essentially constant in the ciliary body for up to 6 hr, declining rapidly only between 6- and 24 hr. 3H activity in eyes that received [3H]PGF2 alpha ME was also several-fold higher in the anterior sclera and iris than in eyes that were treated with [3H]PGF2 alpha free acid, but this difference was much smaller in the conjunctiva. At 1 hr, most of the 3H activity in the aqueous humor was associated with PGF2 alpha, as determined by chromatography, but at 2- and 3 hr other peaks, presumably reflecting metabolites of PGF2 alpha, became apparent. The penetration and intraocular distribution of 3H activity was similar when [3H]PGF2 alpha ME was applied to the eye in normal saline rather than in peanut oil or when the isopropyl rather than the methyl ester of PGF2 alpha was used. These studies indicate that esterification of the carboxyl group of PGF2 alpha greatly enhances the penetration of the PGF2 alpha moiety into the eye and suggests that effective de-esterification of the PGF2 alpha ester occurs in the cornea, resulting in the delivery of PGF2 alpha free acid into the aqueous humor. It is concluded that topically applied PG esters act as pro-drugs and that the increased ocular penetration of these esters may account for the previously reported increase in their ocular hypotensive potency as compared to that of PG free acid or salts.
进行这些实验是为了确定与游离酸形式的前列腺素（PG）PGF2α相比，局部应用的PGF2α酯的眼内降压效力增强是否可归因于酯化PG的类花生酸部分向眼内的渗透增加。在花生油中局部应用[3H]PGF2α - 1 - 甲酯（ME）1小时后，兔眼角膜、房水和睫状体中的3H活性分别比局部应用[3H]PGF2α游离酸后高32倍、22倍和8倍。在最初3小时内，角膜中的3H活性迅速下降，房水中下降较慢，但在睫状体中长达6小时基本保持恒定，仅在6至24小时之间迅速下降。接受[3H]PGF2α ME的眼中，前巩膜和虹膜中的3H活性也比接受[3H]PGF2α游离酸治疗的眼高几倍，但在结膜中这种差异要小得多。通过色谱法测定，在1小时时，房水中的大部分3H活性与PGF2α相关，但在2小时和3小时时，其他峰（可能反映PGF2α的代谢产物）变得明显。当在生理盐水中而非花生油中向眼内应用[3H]PGF2α ME时，或者当使用PGF2α的异丙酯而非甲酯时，3H活性的渗透和眼内分布相似。这些研究表明，PGF2α羧基的酯化极大地增强了PGFα部分向眼内的渗透，并表明PGF2α酯在角膜中发生有效的去酯化，从而将游离酸形式的PGF2α输送到房水中。得出的结论是，局部应用的PG酯起前药作用，与游离酸或盐形式的PG相比，这些酯眼内渗透增加可能解释了先前报道的它们眼内降压效力的增加。
