Isosorbide-based aspirin prodrugs: II. Hydrolysis kinetics of isosorbide diaspirinate

Abstract

Aspirin prodrugs have been intensively investigated in an effort to produce compounds with lower gastric toxicity, greater stability or enhanced percutaneous absorption, relative to aspirin. This report describes the hydrolysis kinetics and aspirin release characteristics of isosorbide diaspirinate (ISDA), the aspirin diester of isosorbide. ISDA underwent rapid hydrolysis when incubated in phosphate buffered human plasma solutions (pH 7.4) at 37 °C, producing appreciable quantities of aspirin. In 30% human plasma solution the half-life was 1.1 min and 61% aspirin was liberated relative to the initial ester concentration. The hydrolysis kinetics of ISDA were monitored in aqueous solution at 37 °C over the pH range 1.03–9.4. The aqueous hydrolysis followed pseudo-first-order kinetics over several half-lives at all pH values, resulting in a U-shaped pH rate profile. Salicylate esters and salicylic acid were formed during these processes. The hydrolysis characteristics of ISDA were also investigated in pH 7.4 phosphate buffered solutions containing α-chymotrypsin [EC 3.1.1.1] ( t 1/2=200.9 min), carboxyl esterase [EC 3.1.1.1] ( t 1/2=31.5 min), human serum albumin ( t 1/2=603 min), purified human serum butyrylcholinesterase [EC 3.1.1.8] (80 μg/ml; t 1/2=9.4 min; 55% aspirin), purified horse serum butyrylcholinesterase (100 μg/ml; t 1/2=1.85 min;11% aspirin) and in 10% human plasma solution in the presence of physostigmine (3 μM). The results indicate that a specific enzyme present in human plasma, probably human butyrylcholinesterase, catalyses aspirin release from isosorbide diaspirinate.