Liver uptake of biguanides in rats.
Liver uptake of biguanides in rats.
复制标题
DOI：
10.1016/j.biopha.2011.04.022
复制
发表时间：
2011-09
期刊：
影响因子：
--
通讯作者：
Y. Sogame;Atsushi Kitamura;M. Yabuki;S. Komuro
中科院分区：
文献类型：
--
作者：
Y. Sogame;Atsushi Kitamura;M. Yabuki;S. Komuro
二甲双胍是一种口服抗高血压药物，广泛用于非胰岛素依赖型糖尿病的治疗。肝脏是主要靶点，二甲双胍通过主动转运机制被人和大鼠肝细胞吸收。本研究旨在比较两种双胍类药物（二甲双胍和苯丙氨酸）在体外和体内的肝脏摄取。在使用大鼠冻存肝细胞进行的体外实验中，苯丙氨酸表现出比二甲双胍高得多的亲和力和转运，动力学存在显著差异。二甲双胍和苯丙氨酸的Km值分别为404和5.17μM，克林特（Vmax/Km）值为1.58μl/min/106个细胞和34.7μl/min/106个细胞。在体内实验中，当14 C-二甲双胍和14 C-苯丙氨酸以50 mg/kg剂量经口给予雄性大鼠时，给药后0.5小时的肝脏放射性浓度为21.5μg eq./kg。g二甲双胍，但147.1μg eq./ g，肝脏与血浆浓度的比值分别为4.2和61.3。总之，结果表明，大鼠肝细胞对双胍类药物的摄取与体内发现的肝脏分布一致，口服给药后，肝脏对苯丙氨酸的摄取比二甲双胍更有效。
Metformin is an oral antihyperglycaemic agent widely used in the management of non-insulin-dependent diabetes mellitus. The liver is the primary target, metformin being taken up into human and rat hepatocytes via an active transport mechanism. The present study was designed to compare hepatic uptake of two biguanides, metformin and phenformin, in vitro and in vivo. In in vitro experiments, performed using rat cryopreserved hepatocytes, phenformin exhibited a much higher affinity and transport than metformin, with marked differences in kinetics. The Kmvalues for metformin and phenformin were 404 and 5.17μM, respectively, with CLint (Vmax/Km) values 1.58μl/min per 106cells and 34.7μl/min per 106cells. In in vivo experiments, when14C-metformin and14C-phenformin were given orally to male rats at a dose of 50mg/kg, the liver concentrations of radioactivity at 0.5 hour after dosing were 21.5μg eq./g with metformin but 147.1μg eq./g for phenformin, ratios of liver to plasma concentrations being 4.2 and 61.3, respectively. In conclusion, the results suggest that uptake of biguanides by rat hepatocytes is in line with the liver distribution found in vivo, phenformin being more efficiently taken up by liver than metformin after oral administration.