阿糖胞苷5′-缬氨酸酯前体药物的小肠吸收机制

Absorption of 5′-O-L-valyl ester of ara-C in rat intestine using in situ single pass perfusion model

目的研究阿糖胞苷的5′-缬氨酸酯前体药物在大鼠小肠内的吸收情况。方法运用单向灌流模型研究药物在小肠内的吸收机制,利用高效液相色谱法测定药物和酚红在灌流液中的浓度。结果阿糖胞苷5′-缬氨酸酯前体药物的小肠渗透率是原药阿糖胞苷的10.6倍,在小肠内的吸收存在浓度依赖性,能够被小肠寡肽转运蛋白的专属底物头孢氨苄明显抑制。结论阿糖胞苷5′-缬氨酸酯前体药物是小肠寡肽转运蛋白的底物,在大鼠小肠内的吸收是由小肠寡肽转运蛋白介导的主动转运过程。

Objective To study the absorption of 5′-valyl-ara-C hydrochloride, a 5′-O-L-valyl ester derivatives of cytarabine（ara-C）. Methods Single pass perfusion model was used to study the absorption of 5′-valyl-ara-C hydrochloride in the absence and presence of inhibitors; concentrations of ara-C, 5′-valyl-ara-C hydrochloride, and phenol red were determined by HPLC. Results The intestinal permeability coefficients of 5′-valyl-ara-C hydrochloride was 12.7 × 10^-2 cm·s^-1, which was 9.6 times higher than that of ara-C. The absorption of 5′-valyl-ara-C hydrochloride in the rat small intestine was a concentration-dependent process and can be significantly inhibited by a substrate of intestinal peptide transporter 1 （PEPT1）, cephalexin. Conclusions 5′-valyl-ara-C hydrochloride is a substrate of PEPT1. The permeation of 5′-valyl-ara-C hydrochloride across the intestinal membrane is a PEPTl-mediated process.