Urea-Based Prodrugs Improve Systemic Mebendazole Exposure After Oral Administration

Background/Objectives: Mebendazole (MBZ) is an established anthelmintic drug with emerging therapeutic potential in oncology and immunology, but its broader clinical utility is constrained by poor aqueous solubility and extensive first-pass metabolism, resulting in low and variable systemic exposure. Methods: Here, we synthesized and profiled in vitro a series of solubility-enhanced, urea-based MBZ prodrugs designed to favor intact absorption across the intestinal epithelium followed by systemic release of parent MBZ. Results: Optimized candidates exhibited markedly improved solubility under simulated intestinal conditions and a favorable metabolic profile, including reduced intestinal metabolism compared with MBZ. In mouse pharmacokinetic studies, oral administration of selected prodrugs increased systemic MBZ exposure relative to equimolar doses of MBZ. Administration of the lead prodrug 2i resulted in an approximately 10-fold higher peak MBZ concentration (Cmax) and approximately 2-fold higher MBZ exposure (area under the plasma concentration–time curve, AUC) compared with an equimolar dose of MBZ. These differences should be interpreted in light of the different dosing formulations, with the prodrug administered as a solution and MBZ as a suspension. Conclusions: These findings provide in vivo proof-of-concept that urea-based prodrugs may improve systemic MBZ exposure following oral administration and support further evaluation of this strategy for indications requiring systemic drug exposure.