在体单向肠灌流模型研究帕拉米韦拟肽类衍生物的大鼠小肠吸收特性

目的研究帕拉米韦及其拟肽类衍生物的大鼠小肠吸收机制,筛选出膜渗透性最大的衍生物。方法采用大鼠在体单向灌流法研究帕拉米韦拟肽类衍生物的小肠吸收,采用高效液相色谱法测定药物和酚红的浓度。建立lgD预测值和lgP之间的关系。结果帕拉米韦拟肽类衍生物的膜渗透系数都比帕拉米韦高,其中帕拉米韦L-异亮氨酸衍生物具有最高的膜渗透性;寡肽转运蛋白(PEPT1)典型底物甘氨酰肌氨酸能显著降低帕拉米韦拟肽类衍生物的小肠吸收,而L-缬氨酸不具有这种能力。结论帕拉米韦拟肽类衍生物是PEPT1的底物,它们在大鼠小肠内的吸收是PEPT1介导的主动转运过程。

Intestinal absorption characteristics of amino acid derivatives of peramivir in rats in vivo by single pass perfusion model

Objective To study intestinal absorption mechanism in rats of amino acid derivatives of peramivir, and to screen the lead compound with the highest permeability. Methods Single pass perfusion model was applied to study the absorption of these derivatives in the absence or presence of PEPT1 inhibitors; and concentrations of these derivatives and phenol red were determined by HPLC method. The correlation between lgD and lgP was also constructed. Results Amino acid derivatives of peramivir had higher permeability than peramivir, and peramivir-L-Ile had the highest permeability. The absorption of all derivatives could be inhibited by Gly-sar, a typical substrates of PEPT1, not by L-valine. Conclusion Amino acid derivatives of peramivir are the substrates of PEPT1, and their permeation across the intestinal epithelium is a PEPT1-mediated process.