Chien D S, Sasaki H, Bundgaard H, Buur A, Lee V H
University of Southern California, School of Pharmacy, Department of Pharmaceutical Sciences, Los Angeles 90033.
Pharm Res. 1991 Jun;8(6):728-33. doi: 10.1023/a:1015845916293.
The main objective of this study was to investigate how enzymatic lability would affect the extent of corneal and conjunctival penetration of a series of alkyl, cycloalkyl, and aryl ester prodrugs of timolol in the pigmented rabbit. Enzymatic lability of the prodrugs was studied in corneal epithelial and conjunctival homogenates, while their corneal and conjunctival penetration was determined using the isolated tissues in the modified Ussing chamber. The straight-chain alkyl and the unsubstituted cycloalkyl esters were hydrolyzed more rapidly than their corresponding branched-chain and substituted analogues as well as the aryl esters. The corneal and conjunctival penetration of all prodrugs, regardless of enzymatic lability, varied parabolically with lipophilicity. Moreover, the enzymatically more labile straight-chain alkyl esters penetrated the cornea and the conjunctiva more readily than the more stable branched-chain esters of comparable lipophilicity. Enzymatic lability is, therefore, an additional factor that should be considered in designing alkyl ester prodrugs with improved ocular drug delivery characteristics. Enzymatic lability does not, however, play as important a role as lipophilicity in the corneal and conjunctival penetration of cycloalkyl and aryl ester prodrugs.
本研究的主要目的是研究酶促不稳定性如何影响一系列噻吗洛尔的烷基、环烷基和芳基酯前药在有色兔眼中角膜和结膜的渗透程度。在前房水和结膜匀浆中研究了前药的酶促不稳定性，同时使用改良的Ussing室中的离体组织测定了它们在角膜和结膜中的渗透性。直链烷基酯和未取代的环烷基酯比它们相应的支链和取代类似物以及芳基酯水解得更快。所有前药的角膜和结膜渗透性，无论酶促不稳定性如何，都随亲脂性呈抛物线变化。此外，酶促更不稳定的直链烷基酯比具有可比亲脂性的更稳定的支链酯更容易穿透角膜和结膜。因此，在设计具有改善眼部药物递送特性的烷基酯前药时，酶促不稳定性是一个应考虑的额外因素。然而，在环烷基和芳基酯前药的角膜和结膜渗透中，酶促不稳定性不像亲脂性那样起重要作用。
