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Studies on absorption mechanism and pharmacokinetic properties of albendazole-bile acid conjugate: In vivo and in vitro.
Guo, Zhimei; Tang, Shizhen; Nie, Kaili; Liu, Jingshuai; Hu, Chunhui.
Afiliación
  • Guo Z; State Key Laboratory of Plateau Ecology and Agriculture, Qinghai University, Xining, Qinghai 810001, PR China; Medical College, Qinghai University, Xining, Qinghai 810001, PR China.
  • Tang S; State Key Laboratory of Plateau Ecology and Agriculture, Qinghai University, Xining, Qinghai 810001, PR China; Medical College, Qinghai University, Xining, Qinghai 810001, PR China.
  • Nie K; College of Life Science and Technology, Beijing University of Chemical of Technology, Beijing 100086, PR China.
  • Liu J; College of Life Science and Technology, Beijing University of Chemical of Technology, Beijing 100086, PR China.
  • Hu C; State Key Laboratory of Plateau Ecology and Agriculture, Qinghai University, Xining, Qinghai 810001, PR China. Electronic address: chunhuihu@hotmail.com.
Biomed Pharmacother ; 179: 117400, 2024 Sep 06.
Article en En | MEDLINE | ID: mdl-39243427
ABSTRACT

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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Biomed Pharmacother Año: 2024 Tipo del documento: Article Pais de publicación: Francia
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Biomed Pharmacother Año: 2024 Tipo del documento: Article Pais de publicación: Francia