Muranushi N, Hashimoto N, Hirano K
Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Pharm Res. 1995 Oct;12(10):1488-92. doi: 10.1023/a:1016287421436.
Elucidating the transport characteristics of S-1090, a new orally active cephalosporin in rat small intestinal brush-border membranes.
A rapid filtration technique.
The uptake of S-1090 was stimulated by an inwardly directed H(+)-gradient, but did not show overshooting uptake. To investigate the transport system, the inhibitory and countertransport effects of various compounds on S-1090 uptake were examined. Although the dipeptides and tripeptides composed of amino acids with aliphatic side chains did not inhibit the uptake of S-1090, those having histidine, proline or tryptophan as the N-terminal amino acid showed an inhibitory effect. Among the oral cephems tested, ceftibuten showed marked inhibition, while cefaclor and cephalexin had no inhibitory effect. Countertransport effects on S-1090 uptake were observed only when the vesicles were preloaded with histidyl peptides such as His-Gly or His-Ala, while other compounds which exhibited inhibition had no countertransport effect.
Based on the above results, there seems to be heterogeneity (multiplicity) in the oligopeptide transport system which may depend on the structure of the N-terminal amino acid. S-1090 may be dominantly transported via a system that recognizes peptides having histidine as the N-terminal amino acid.
阐明新型口服活性头孢菌素S-1090在大鼠小肠刷状缘膜中的转运特性。
采用快速过滤技术。
S-1090的摄取受到内向H⁺梯度的刺激，但未表现出过冲摄取。为研究转运系统，检测了各种化合物对S-1090摄取的抑制和反向转运作用。由具有脂肪族侧链的氨基酸组成的二肽和三肽虽不抑制S-1090的摄取，但以组氨酸、脯氨酸或色氨酸作为N端氨基酸的那些二肽和三肽表现出抑制作用。在所测试的口服头孢菌素中，头孢布烯表现出明显抑制作用，而头孢克洛和头孢氨苄则无抑制作用。仅当囊泡预先装载有组氨酸肽如His-Gly或His-Ala时，才观察到对S-1090摄取的反向转运作用，而其他表现出抑制作用的化合物则无反向转运作用。
基于上述结果，寡肽转运系统似乎存在异质性（多样性），这可能取决于N端氨基酸的结构。S-1090可能主要通过识别以组氨酸作为N端氨基酸的肽的系统进行转运。
