强效口服活性人肾素抑制剂瑞米吉仑在实验动物体内的分布。

Distribution of remikiren, a potent orally active inhibitor of human renin, in laboratory animals.

Richter W F, Whitby B R, Chou R C

Pharma Division, F. Hoffmann-La Roche AG, Basel, Switzerland.

Xenobiotica. 1996 Mar;26(3):243-54. doi: 10.3109/00498259609046705.

Abstract

Whole-body autoradiography was used to compare the distribution of remikiren in the squirrel monkey, in which the compound is a potent inhibitor of renin, with the rat and the guinea-pig in which it is less active. 2. Following intravenous administration, drug-related material was rapidly and extensively taken up by the tissues of all three species. Consistent with rapid biliary elimination, high levels of radioactivity were found in the bile duct/gall bladder/intestinal contents. Of the remaining organs, the kidney consistently showed the highest concentrations of drug-related material. 3. Radio-hplc analysis of the kidney samples demonstrated that the majority of the retained material was present as intact remikiren, even at 24 h after administration. A similar degree of retention by the kidney was also found after oral dosing. 4. Uptake of remikiren by the kidney may act as a reservoir for the drug, resulting in the prolonged duration of pharmacological activity, which, despite the high plasma clearance of the drug, has previously been observed in primates.

摘要

采用全身放射自显影技术，比较瑞米吉仑（remikiren）在松鼠猴体内的分布情况（该化合物在松鼠猴体内是肾素的强效抑制剂），并与它在大鼠和豚鼠体内的分布情况进行对比（在大鼠和豚鼠体内其活性较低）。2. 静脉给药后，药物相关物质迅速且广泛地被这三种动物的组织摄取。与快速经胆汁消除一致，在胆管/胆囊/肠内容物中发现了高水平的放射性。在其余器官中，肾脏始终显示出最高浓度的药物相关物质。3. 对肾脏样本进行放射性高效液相色谱分析表明，即使在给药后24小时，保留物质的大部分仍以完整的瑞米吉仑形式存在。口服给药后，肾脏也有类似程度的保留。4. 肾脏对瑞米吉仑的摄取可能作为药物的储存库，导致药理活性持续时间延长，尽管该药物的血浆清除率较高，但此前在灵长类动物中已观察到这种情况。