In vitro hydrolysis of novel gamma-linolenoyloxyalkyl derivatives of theophylline

Abstract A variety of N -gamma-linolenoyloxyalkyl derivatives of theophylline were prepared to determine the effect of varying the nature of the alkyl linkage on in vitro rates of hydrolysis catalyzed by using porcine esterase and human plasma. All derivatives displayed first-order hydrolysis kinetics in 80% human plasma. The chiral theophylline derivatives displayed a biexponential hydrolysis profile using porcine esterase suggesting this enzyme is capable of chiral resolution. The susceptibility of the derivatives to undergo hydrolysis varied widely with half-lives ranging from 7.0 to 711 min using porcine esterase and 19.5 min to over 40 h using human plasma. The rate at which these theophylline derivatives were hydrolyzed depended on the nature of the group linking theophylline and gamma-linolenic acid. The rate of hydrolysis occurred in decreasing order with the following linking moieties: methyl>ethyl>propyl>butyl>isobutyl>pentyl>pivalyl. Overall the results demonstrate that the rate of hydrolysis by porcine esterase and human plasma of N -gamma-linolenoyloxyalkyl theophylline derivatives can be slowed by increasing the steric hindrance of the alkyl moieties. The rates of hydrolysis of these theophylline derivatives follow a predictable pattern based on the steric hindrance of the linking group. A linear correlation was obtained between log t 1/2 using the effective number of carbons in the linker, C B (the number of carbons in the linker plus 0.5 for each branch). A similar trend was observed between log t 1/2 and the standard Charton steric parameter, ν .