A study on the in vitro stability and metabolism of curcumin diethyl disuccinate in plasma

Abstract

Stability in aqueous media such as buffers and plasma are the one of important properties of drug candidates. Curcumin diethyl disuccinate (CDD), an ester prodrug of curcumin, has been developed to improve the chemical stability of curcumin. In this study, the in vitro stability of CDD in HCl buffer (pH 1.2), acetate buffer (pH 4.5), phosphate buffer (pH 6.8, 7.4 and 8.0) and in vitro metabolism of CDD in rat, dog and human plasma were investigated at 4, 25 and 37 °C. HPLC and nonlinear regression analyses showed that the degradation of CDD in buffers was temperature-dependent and followed pseudo-1st order kinetics. CDD was least stable in acetate buffer at all tested temperatures. The plasma metabolism of CDD was temperature-dependent and the reaction followed consecutive pseudo-1st order kinetics. The CDD hydrolysis in plasma was accelerated by plasma esterases in the following order: rat >> human > dog. LC-MS/MS analysis showed that the cleavage of ester bonds of CDD was preferential at the phenolic ester, producing monoethylsuccinyl curcumin as the intermediate metabolite. The use of various esterase inhibitors indicated that carboxylesterase was the enzyme involving CDD hydrolysis in rat plasma while multiple enzymes played a role in dog and human. This study provides useful information for future in vivo studies and further development of CDD as a therapeutic agent.