Effect of Food on the Intestinal PEPT1-mediated Drug Absorption

在本研究中，我们发现，奥司他韦，神经氨酸酶抑制剂[3R，4 R，5S]-4-乙酰氨基-5-氨基-3-（1-乙基丙氧基）-1-环己烯-1-羧酸（Ro 64-0802）的酯型前体药物，在体外被PEPT 1有效吸收，同时给予牛奶、酪蛋白或甘氨酰肌氨酸可大大降低大鼠对奥司他韦的吸收。此外，在健康志愿者中进行的临床研究表明，牛奶显著降低了奥司他韦和Ro 64-0802的最大血浆浓度（Cmax）和0 - 2小时血浆浓度-时间曲线下面积（AUC 0 -2）。然而，相互作用的程度在大鼠和人类之间是不同的，这可能是因为PEPT 1表达及其贡献的种属差异。在大鼠体内也观察到已知PEPT 1底物的相同相互作用。这可能是第一个发现，表明临床药物-食物相互作用通过PEPT 1。

In the present study, we found that oseltamivir, an ester-type prodrug of neuraminidase inhibitor [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene -1-carboxylic acid (Ro 64-0802), was effectively taken up by PEPT1 in vitro and that oseltamivir absorption in rats was greatly reduced by simultaneous administration of milk, casein , or glysylsarcosin. In addition, clinical stud iesin healthy volunteers showed that milk significantly reduced the maximum plasma concentrations (Cmax) and the area under the plasma concentration -time curves from 0 to 2 hour (AUC0-2) of both oseltamivir and Ro 64-0802. However, the extent of interaction was different between rats and humans, possibly because of sepecies difference in the PEPT1 expression and its contribution. Same interactions for known PEPT1 substrates were also seen in rat in vivo. These might be a first finding that suggests clinical drug-food interaction via PEPT1.