The Study Of Synthesis Degradation Dynamics And Pharmacokinetics Of L-dopa Ester Acetylation In Rat

Objective: To design and synthesize (S)-4-(2-acetamido-3-ethoxy-3 -oxopropyl)-1,2-phenylene diacetate(AEPD)utilizing the principle of prodrug, to study the dynamics of its degradation in vitro and the pharmacokinetics of AEPD in rats.Methods: AEPD was prepared with levodopa as raw materials throwing esterification and acetylation. The structure of the compound was confirmed by MS, IR, UV, 1H-NMR, 13C-NMR.The dynamics of its aqueous solutions in vitro were studied under the following conditions: pH 1.3, pH 5.0, pH 7.4 (temperature: 37℃) . An HPLC-MS/MS method had been developed and validated for the simultaneous determination of L-dopa and its prodrug AEPD in rat plasma. The method was used to study the pharmacokinetics of L-dopa and AEPD in rats.Results: The crystalline product is while with a purity exceeding 99.5%. The product structure is (S)-4-(2-cetamido-3-ethoxy-3-oxopropy)-1, 2-phenylene diacetate. The half lives of AEPD aqueous solutions at pH 1.3, pH 5.0, pH 7.4 (temperature: 37℃) are 31,330 ,7 h, respectively. The HPLC-MS/MS method is simple, rapid, accurate and is able to determinate the content of L-dopa and its prodrug AEPD in vivo. The parameters (T_{1/2 Ke},AUC) of L-dopa after administration of AEPD are larger significantly than after administration of L-dopa.Conclusion: The structure of the product is consistent with the design one. The aqueous solutions of AEPD is stable under the condition of pH1.3, pH 5.0, pH 7.4 (temperature: 37℃), it shows than it is stable before entering the internal circulation. L-dopa prodrug AEPD is able to increase the bioavailability and lengthen the half life of L-dopa.