Mochizuki T, Jansen F P, Leurs R, Windhorst A D, Yamatodani A, Maeyama K, Timmerman H
Department of Pharmacology, Ehine University School of Medicine, Japan.
Brain Res. 1996 Dec 16;743(1-2):178-83. doi: 10.1016/s0006-8993(96)01040-2.
We investigated the brain penetration of the histamine H3 receptor antagonists thioperamide and clobenpropit using ex vivo [125I]iodophenpropit binding. Homogenates of the rat cortex, striatum and mouse whole brain were prepared 1 h after subcutaneous injection of the H3 antagonists and incubated with [125I]iodophenpropit, a radiolabeled H3 receptor antagonist, to determine the H3 receptor occupancy. Specific [125I]iodophenpropit binding to the rat cortex and striatum was inhibited by thioperamide with IC30 values of 1.0 and 1.5 mg/kg, respectively. Clobenpropit also inhibited [125I]iodophenpropit binding, but was less potent (IC30: 18 and 19 mg/kg in the rat cortex and striatum, respectively) than thioperamide. Similar results were obtained in experiments with mouse whole brain (3.5 and 13 mg/kg for thioperamide and clobenpropit), indicating that there is no important species differences in the brain penetration of these drugs between rats and mice. These findings suggest that after peripheral injection both in rat and mouse thioperamide penetrates the blood-brain barrier more efficiently compared to clobenpropit.
我们使用离体[125I]碘苯丙胺结合法研究了组胺H3受体拮抗剂硫代哌酰胺和氯苯丙胺的脑渗透情况。在皮下注射H3拮抗剂1小时后制备大鼠皮质、纹状体和小鼠全脑的匀浆，并与放射性标记的H3受体拮抗剂[125I]碘苯丙胺孵育，以确定H3受体占有率。硫代哌酰胺抑制了[125I]碘苯丙胺与大鼠皮质和纹状体的特异性结合，IC30值分别为1.0和1.5 mg/kg。氯苯丙胺也抑制了[125I]碘苯丙胺的结合，但效力低于硫代哌酰胺（大鼠皮质和纹状体的IC30分别为18和19 mg/kg）。在小鼠全脑实验中也得到了类似的结果（硫代哌酰胺和氯苯丙胺分别为3.5和13 mg/kg），表明大鼠和小鼠之间这些药物的脑渗透不存在重要的物种差异。这些发现表明，在大鼠和小鼠外周注射后，与氯苯丙胺相比，硫代哌酰胺更有效地穿透血脑屏障。
