Synthesis and in vitro kinetic study of new mutual prodrug for colon cancer associated with constipation

Objective: a new mutual prodrug was synthesized for colon targeting in the treatment of colon cancer associated with constipation. Methods: a new mutual prodrug was synthesized through several steps included amide hydrolysis in a strong acidic medium, amide synthesis, diazotization and coupling reactions. The stability of this prodrug in HCl buffer, in phosphate buffer and in rat fecal matter was monitored. The chemical structure of mutual prodrug was characterized by physical and spectroscopic techniques as FTIR, UV-Visible and 13C NMR spectra. In colon, the mutual prodrug was proposed to split by the action of bacterial azoreductase into two N-substituted benzamides, metoclopramide and declopramide, that constituted two apoptotic agents, also the local application of metoclopramide on colonic smooth muscles was proposed to enhance their contractions affords relief of constipation. In vitro kinetic studies in a hydrochloric acid buffer showed an insignificant release of metoclopramide and declopramide while in a phosphate buffer, only (9.12٪) release was observed over six hours. In order to confirm the hydrolysis of mutual prodrug in colon, the release study in a rat fecal matter was monitored over six hours and showed that the hydrolysis was almost complete (90.88٪) with a half-life of (166.19 min) followed first order kinetics. The prodrug approach that is based on enzymes specification may offer a new method to improve drug efficacy and reduce side effects.