IN-VITRO HYDROLYSIS OF NOVEL GAMMA-LINOLENOYLOXYALKYL DERIVATIVES OF THEOPHYLLINE

A variety of N-gamma-linolenoyloxyalkyl derivatives elf theophylline w ere prepared to determine the effect of varying the nature of the alky l linkage on in vitro rates of hydrolysis catalyzed by using porcine e sterase and human plasma. All derivatives displayed first-order hydrol ysis kinetics in 80% human plasma. The chiral theophylline derivatives displayed a biexponential hydrolysis profile using porcine esterase s uggesting this enzyme is capable of chiral resolution. The susceptibil ity of the derivatives to undergo hydrolysis varied widely with half-l ives ranging from 7.0 to 711 min using porcine esterase and 19.5 min t o over 40 h using human plasma. The rate at which these theophylline d erivatives were hydrolyzed depended on the nature of the group linking theophylline and gamma-linolenic acid. The rate of hydrolysis occurre d in decreasing order with the following linking moieties: methyl > et hyl > propyl > butyl > isobutyl > pentyl > pivalyl. Overall the result s demonstrate that the rate of hydrolysis by porcine esterase and huma n 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 predict able pattern based on the steric hindrance of the linking group. A lin ear correlation was obtained between log t(1/2) using the effective nu mber of carbons in the linker, C-B (the number of carbons in the linke r plus 0.5 for each branch). A similar trend was observed between log t(1/2) and the standard Charton steric parameter, v. (C) 1997 Elsevier Science B.V.