Albendazole oral drug delivery through ASBT-mediated cholic acid derivatives: A win-win for solubility and permeability

•Abendazole-bile acid derivatives can effectively improve the solubility and permeability of drugs, achieving a win-win effect for both.•The intervention of bile acid can make albendazole exist in an amorphous state, laying a molecular foundation for its solubilization.•Based on the specific recognition of bile acid by the apical membrane sodium dependent bile acid transporter (ASBT), the transmembrane transport efficiency of drugs can be increased. This study investigates the transmembrane transport of cholic acids through the primary sodium-dependent cholic acid transporter (ASBT) and explores the synthesis of a series of albendazole cholic acid derivatives (ABZ-CA). These derivatives, incorporating various linker lengths, aim to enhance the solubility and permeability of albendazole (ABZ) simultaneously. We systematically examined the structural and physicochemical properties of ABZ-CA, delving into its transmembrane transport mechanism and assessing its efficacy against Echinococcus multilocularis (E. multilocularis). Our investigation demonstrates the successful preparation of ABZ-CA using amino alcohols as linkers. The apparent solubility ranking of ABZ-CAs is as follows: ABZ-C4 > ABZ > ABZ-C8 ≈ ABZ-C1. This ranking reflects a balance between the solubilization effect induced by the amorphous state of ABZ-CA and the hydrophobic effect resulting from increased linker length. Enhanced absorption of ABZ-CAs is observed throughout all segments of the intestine, indicating a mechanism of passive diffusion. Notably, the optimal site for absorption shifts from the jejunum (ABZ) to the ileum (ABZ-CAs), with ASBT inhibitors significantly reducing the efficiency of transmembrane transport of ABZ-CAs in the ileum. This implies a specific mechanism of active transport reliant on ASBT. Our hypothesis is that ABZ-CAs undergo transmembrane transport in the gastrointestinal tract via a dual mechanism involving both passive diffusion and active transport. In pharmacodynamic studies, the inclusion of cholic acids does not affect the anti-E. multilocularis effect. Therefore, we believe that the formulation of ABZ-CAs not only enhances the solubility of ABZ but also increases its permeability, resulting in a synergistic effect. Moreover, this formulation presents a novel approach for enhancing the solubility and gastrointestinal permeability of BCSII and IV drugs during oral administration, consequently improving their oral bioavailability.