Abstract
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.
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