阿苯达唑-胆酸轭合物的吸收机制和药代动力学性质的研究：体内和体外。
Studies on absorption mechanism and pharmacokinetic properties of albendazole-bile acid conjugate: In vivo and in vitro.
机构信息
State Key Laboratory of Plateau Ecology and Agriculture, Qinghai University, Xining, Qinghai 810001, PR China; Medical College, Qinghai University, Xining, Qinghai 810001, PR China.
College of Life Science and Technology, Beijing University of Chemical of Technology, Beijing 100086, PR China.
出版信息
Biomed Pharmacother. 2024 Oct;179:117400. doi: 10.1016/j.biopha.2024.117400. Epub 2024 Sep 8.
PURPOSE
To improve the oral bioavailability of albendazole (ABZ), a series of albendazole-bile acid conjugates (ABCs) were synthesized. ABC's transmembrane transport mechanism and in vivo pharmacokinetic properties were preliminarily studied.
METHODS
The transmembrane transport mechanism of ABCs was studied using the Caco-2 monolayer cell model and intestinal perfusion model. The concentration of ABCs and ABZ were evaluated using High-Performance Liquid Chromatography (HPLC) and HPLC-Mass Spectrometry (HPLC-MS/MS).
RESULTS
Compared to ABZ, better permeability was observed for different types and concentrations of ABCs using the Caco-2 monolayer cell model, with ABC-C8 showing the highest permeability. The transmembrane transport of ABCs was affected by ASBT inhibitors, indicating an ASBT-mediated active transport mechanism. Additionally, introducing cholic acid resulted in ABZ no longer being a substrate for P-gp, MRP2, and BCRP, effectively reversing ABZ efflux. In vivo unidirectional intestinal perfusion results in rats showed that ABCs altered the absorption site of ABZ from the jejunum to the ileum. The absorption efficiency of ABCs in each intestinal segment was higher than that of ABZ, and the transmembrane transport efficiency decreased with increasing concentrations of ASBT inhibitors. This further confirmed the presence of both passive diffusion and ASBT-mediated active transport mechanisms in the transport of ABCs. The solubility of ABCs in gastric juice and pharmacokinetics in rats showed that ABZ-C4 exhibited enhanced solubility. Moreover, ABCs significantly increased oral bioavailability compared to ABZ, with ABC-C4 showing an approximately 31-fold increase in bioavailability.
CONCLUSION
The transmembrane transport mechanism of ABCs involves a combination of ASBT-mediated active transport and passive diffusion. Moreover, the incorporation of BAs successfully reverses the efflux of ABZ by efflux proteins. Among the synthesized conjugates, ABC-C4 demonstrated superior dissolution behavior both in vitro and in vivo.
目的
为提高阿苯达唑（ABZ）的口服生物利用度，合成了一系列阿苯达唑-胆酸缀合物（ABCs）。初步研究了 ABC 的跨膜转运机制和体内药代动力学性质。
方法
采用 Caco-2 单层细胞模型和肠灌流模型研究 ABC 的跨膜转运机制。采用高效液相色谱法（HPLC）和高效液相色谱-质谱联用（HPLC-MS/MS）测定 ABC 和 ABZ 的浓度。
结果
与 ABZ 相比，不同类型和浓度的 ABC 在 Caco-2 单层细胞模型中表现出更好的通透性，其中 ABC-C8 的通透性最高。ABC 的跨膜转运受 ASBT 抑制剂的影响，表明存在 ASBT 介导的主动转运机制。此外，引入胆酸可使 ABZ 不再成为 P-gp、MRP2 和 BCRP 的底物，有效逆转 ABZ 的外排。在大鼠体内单向肠灌流结果中，ABC 改变了 ABZ 的吸收部位，从空肠转移到回肠。ABC 在各肠段的吸收效率均高于 ABZ，且随着 ASBT 抑制剂浓度的增加，跨膜转运效率降低。这进一步证实了 ABC 转运中存在被动扩散和 ASBT 介导的主动转运机制。ABC 在胃液中的溶解度和大鼠体内的药代动力学结果表明，ABZ-C4 具有增强的溶解度。此外，与 ABZ 相比，ABC 显著提高了口服生物利用度，ABZ-C4 的生物利用度增加了约 31 倍。
结论
ABC 的跨膜转运机制涉及 ASBT 介导的主动转运和被动扩散的结合。此外，胆酸的掺入成功逆转了外排蛋白对 ABZ 的外排。在所合成的缀合物中，ABZ-C4 在体外和体内均表现出优越的溶解行为。
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