环糊精包合作用对在体大鼠肠道P-糖蛋白药泵的影响

目的研究环糊精包合作用对P-糖蛋白底物药物体内吸收的影响。方法以P-糖蛋白底物盐酸小檗碱为模型药物,使用大鼠在体单向肠灌流装置,采用高效液相色谱法分别测定灌流液中盐酸小檗碱和酚红的浓度变化;研究2-羟丙基-β-环糊精(HP-β-CyD)对盐酸小檗碱肠道吸收的影响,以此评价环糊精包合作用对P-糖蛋白药泵的影响。结果盐酸小檗碱、盐酸小檗碱/HP-β-CyD物理混合物及盐酸小檗碱/HP-β-CyD包合物在大鼠空肠的吸收速率常数(Ka)分别为(0.45±0.029)、(0.70±0.087)、(2.39±0.119)×10-2·min-1,有效渗透系数(Peff)分别为(0.43±0.028)、(0.63±0.098)、(2.17±0.145)×10-3min·cm-1。HP-β-CyD对盐酸小檗碱的包合作用促进了大鼠肠道对盐酸小檗碱吸收。HP-β-CyD与盐酸小檗碱混合给药也能促进药物的吸收,但其作用远低于包合作用。结论环糊精的包合作用将有可能成为提高P-糖蛋白底物药物生物利用度的有效手段。

Influence of 2-hydroxypropyl-beta-cyclodextrin complexation on P-glycoprotein drug pump in the intestine of rats

Aim To explore the influence of 2-hydroxypropyl-beta-cyclodextrin (HP-β-CyD) on the intestinal transport of the drugs which were P-glycoprotein substrates.Methods The intestinal transport of berberine hydrochloride used as model drug of P-glycoprotein substrate was investigated using the single pass intestinal perfusion (SPIP) technique in Sprague-Dawley male rats.SPIP was performed in the intestinal segment of jejunum with the concentration of 20 mg·L-1 at a flow rate of 0.2 ml·min-1.The contents of berberine hydrochloride and phenol red in perfusion solution were quantified by HPLC method.Preliminary binding and stability studies were conducted to ensure that the loss of berberine hydrochloride in the SPIP study could be attributed to intestinal absorption.The absorption rate constants (Ka) and effective permeability (Peff) of berberine hydrochloride were determined.Results Absorption rate constants(Ka) in rat jejunum for berberine hydrochloride,berberine hydrochloride/HP-β-CyD physical mixture and berberine hydrochloride/HP-β-CyD inclusion complexes were calculated to be (0.45±0.029),(0.70±0.087),(2.39±0.119)×10-2·min-1,respectively.The effective intestinal permeability (Peff) across rat jejunum was calculated to be (0.43±0.028),(0.63±0.098),(2.17±0.145)×10-3 min·cm-1,respectively.Berberine hydrochloride/HP-β-CyD inclusion complexes could greatly improve the berberine hydrochloride absorption in the small intestine of rats.Conclusion The inclusion behavior of cyclodextrins to drugs as P-glycoprotein substrates might lead to shielding of these drug molecules from efflux pumps.