Preparation,characterization,transmembrane transport,and degradation evaluation of albendazole cholic acid derivatives
Objective To improve the transcellular transport efficiency of albendazole(ABZ)by preparing a novel compound,ABZ-C6O2-BA,based on the specific recognition of the apical sodium-dependent bile acid transporter(ASBT)for bile acid(BA).The solid state properties,transcellular transport behavior,and degradation mechanism of ABZ-C6O2-BA were evaluated.Method ABZ-C6O2-BA was synthesized by linking ABZ with BA using 6-aminodihydroxy-dipentyl glycerol as the linker.The synthesized ABZ-C6O2-BA was verified by 1H-NMR and FT-IR.The solid state properties were characterized by powder X-ray diffraction(PXRD),differential scanning calorimetry(DSC),and scanning electron microscopy(SEM).The transcellular transport behavior of ABZ-C6O2-BA was studied in vitro using a Caco-2 monolayer cell model.The degradation mechanism of ABZ-C6O2-BA was evaluated by in vitro carboxylesterase(CES)hydrolysis,and the hydrolysis products were quantitatively analyzed by ultra-high-performance liquid chromatography-mass spectrometry(UPLC-MS).Results The 1H-NMR and FT-IR results showed a shift in characteristic peaks,confirming the successful synthesis of ABZ-C6O2-BA.The PXRD,DSC,and SEM results showed that ABZ-C6O2-BA was amorphous in form,and its microstructure was significantly different from that of ABZ.The in vitro transcellular transport experiment results showed that the apparent permeability coefficient(Papp)of high-quality ABZ-C6O2-B A across the membrane was significantly higher than that of high-concentration ABZ(P＜0.05),and the Papp of medium-and low-quality ABZ-C6O2-BA was similar to that of ABZ.The degradation rate of ABZ-C6O2-BA was＞92.8％at 72 h.By UPLC-MS qualitative analysis,the hydrolysis product of ABZ-C6O2-BA was identified as ABZ-Linker,indicating that the CES hydrolyzed the ester bond,separating BA from ABZ.Conclusion The ABZ-C6O2-BA prepared in this study exists in an amorphous state,and its transmembrane transport efficiency is significantly increased at certain concentrations,which is independent of the concentration,suggesting that the transmembrane mode is active transport.The connected BA can be hydrolyzed by enzymes in the body.
albendazolecholic acidapical sodium-dependent bile salt transporter(ASBT)Caco-2 cellstransmembrane transportdegradation
NETL
NSTL
万方数据
