Itagaki Shirou, Saito Yoshitaka, Kubo Sayaka, Otsuka Yukio, Yamamoto Yuta, Kobayashi Masaki, Hirano Takeshi, Iseki Ken
Department of Clinical Pharmaceutics and Therapeutics, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo 060-0812, Japan.
J Pharmacol Exp Ther. 2005 Jan;312(1):77-82. doi: 10.1124/jpet.104.074021. Epub 2004 Aug 17.
(-)-N-(trans-4-Isopropylcyclohexanecarbonyl)-D-phenylalanine (nateglinide) is a novel oral hypoglycemic agent possessing a carboxyl group and a peptide-type bond in its structure. Although nateglinide quickly reaches the maximal serum concentration after oral administration, nateglinide itself is not transported by PepT1 or MCT1. The aim of this study was to characterize the transporters on the apical side of the small intestine that are responsible for the rapid absorption of nateglinide. The uptake of nateglinide by rat intestinal brush-border membrane vesicles is associated with a proton-coupled transport system. Ceftibuten competitively inhibited H(+)-dependent nateglinide uptake. Glycylsarcosine (Gly-Sar), cephradine, and cephalexin did not significantly inhibit the uptake of nateglinide. The combination of Gly-Sar and nateglinide greatly reduced the uptake of ceftibuten. The effect of the combined treatment was significantly greater than that of Gly-Sar alone. Furthermore, nateglinide competitively inhibited H(+)-driven ceftibuten transporter-mediated ceftibuten uptake. Ceftibuten transport occurs via at least two H(+)-dependent transport systems: one is PepT1, and the other is the ceftibuten/H(+) cotransport system. On the other hand, we demonstrated that nateglinide transport occurs via a single system that is H(+) dependent but is distinct from PepT1 and may be identical to the ceftibuten/H(+) cotransport system.
(-)-N-(反式-4-异丙基环己烷羰基)-D-苯丙氨酸（那格列奈）是一种新型口服降糖药，其结构中含有羧基和肽型键。尽管那格列奈口服给药后能迅速达到最大血清浓度，但那格列奈本身并非由肽转运体1（PepT1）或单羧酸转运体1（MCT1）转运。本研究的目的是鉴定负责那格列奈快速吸收的小肠顶端侧转运体。大鼠肠刷状缘膜囊泡对那格列奈的摄取与质子偶联转运系统有关。头孢布烯竞争性抑制H⁺依赖性那格列奈的摄取。甘氨酰肌氨酸（Gly-Sar）、头孢拉定和头孢氨苄对那格列奈的摄取无明显抑制作用。Gly-Sar与那格列奈联合使用大大降低了头孢布烯的摄取。联合治疗的效果明显大于单独使用Gly-Sar的效果。此外，那格列奈竞争性抑制H⁺驱动的头孢布烯转运体介导的头孢布烯摄取。头孢布烯的转运至少通过两种H⁺依赖性转运系统进行：一种是PepT1，另一种是头孢布烯/H⁺共转运系统。另一方面，我们证明那格列奈的转运通过单一系统进行，该系统依赖H⁺，但不同于PepT1，可能与头孢布烯/H⁺共转运系统相同。
