Influence of chain length on the in vitro hydrolysis of model ester prodrugs by ocular esterases

Abstract

In designing ester prodrugs to improve corneal drug bioavailability, it is important to consider the influence of chain length on both corneal permeation and hydrolysis of the prodrug. However, the second factor has received relatively little attention. The purpose of this study was to evaluate whether the ocular hydrolysis of a homologous series of α-and β-napthyl esters was influenced by chain length. Solutions of each ester were incubated with selected ocular tissues and fluids of adult albino rabbits. For the α-series peak hydrolytic rate was reached at the caproate (C6) ester, coinciding with minimization in the value of the Michaelis-Menten constant (Km) and maximization in the value of maximum velocity (Vmax). For the β-series peak hydrolytic rate was reached at the valerate (C5) ester. In contrast to the α-series this was primarily due to a large increase in value for Km. These findings indicate that the rate of ocular esterase-mediated hydrolysis varies within a homologous series of esters, and that this chain length dependency is influenced by the chemical nature of the parent compound.