Design and Evaluation of Ethylene Glycol Monopiperate as a Novel Antihyperlipidemic Prodrug: Synthesis, Antihyperlipidemic Activity, and Pharmacokinetics

Piperine, a major active component isolated from the traditional Mongolian medicine Piper longum L. , exhibits antihyperlipidemic activity but also demonstrates inherent toxicity. In this study, ethylene glycol monopiperate (EGM), a piperine derivative, was synthesized via concentrated H ₂ SO ₄ ‐catalyzed esterification. Its structure was systematically characterized by FTIR, MS, ¹³ C NMR, and ¹ H NMR, with a yield of 60% and a purity of 99.2%. Subsequently, the in vitro cytotoxicity of EGM on HepG2 cells was evaluated, and the results indicated that over 90% cell viability was observed at concentrations up to 150 μg/mL. It was also investigated in male Wistar rats, and a sensitive, rapid, and accurate solid‐phase extraction (SPE)–UPLC method was developed and validated for the quantification of EGM in rat plasma. The novel method showed good linearity over the concentration range of 1–16 µg/mL, a limit of detection (LOD) of 1 μg/mL, and high accuracy and precision (relative error [RE%] < 15%, relative standard deviation [RSD%] < 10%). In terms of antihyperlipidemic efficacy, EGM demonstrated excellent performance in reducing total cholesterol (TC), glucose (GLU), and low‐density lipoprotein cholesterol (LDL‐C), as well as elevating high‐density lipoprotein cholesterol (HDL‐C); these effects were notably better than the conventional control drug simvastatin. Pharmacokinetic analysis revealed that the plasma concentration‐time profile of EGM followed a first‐order open one‐compartment model. Calculations using WINNONLIN software (ver. 5.2) showed a half‐life ( t _1/2 ) of 1.46 ± 0.67 h and an area under the curve (AUC ₀ –∞) of 7,15,530 ± 522.4 ng h/mL. EGM was stable in plasma over 24 h at room temperature and one month at −20°C, after three freeze–thaw cycles. These results verified that EGM may serve as a promising candidate for an antihyperlipidemic prodrug.