Pharmacokinetics Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd. 1-98 Kasugade-naka 3-chome, Konohana-ku, Osaka 554-0022, Japan.
Biomed Pharmacother. 2011 Sep;65(6):451-5. doi: 10.1016/j.biopha.2011.04.022. Epub 2011 Jun 12.
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 K(m) values for metformin and phenformin were 404 and 5.17μM, respectively, with CLint (V(max)/K(m)) values 1.58μl/min per 10(6) cells and 34.7μl/min per 10(6) cells. In in vivo experiments, when (14)C-metformin and (14)C-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.
二甲双胍是一种广泛用于治疗非胰岛素依赖型糖尿病的口服抗高血糖药物。肝脏是主要的靶器官，二甲双胍通过主动转运机制被摄取到人和大鼠肝细胞中。本研究旨在比较两种双胍类药物二甲双胍和苯乙双胍在体外和体内的肝摄取。在使用大鼠冷冻保存肝细胞进行的体外实验中，苯乙双胍表现出比二甲双胍更高的亲和力和转运能力，动力学差异明显。二甲双胍和苯乙双胍的 K(m)值分别为 404 和 5.17μM，CLint（V(max)/K(m)）值分别为 1.58μl/min per 10(6)细胞和 34.7μl/min per 10(6)细胞。在体内实验中，当雄性大鼠以 50mg/kg 的剂量口服给予 (14)C-二甲双胍和 (14)C-苯乙双胍时，给药后 0.5 小时肝脏中的放射性浓度分别为 21.5μg eq./g 与二甲双胍，但为 147.1μg eq./g 与苯乙双胍，肝与血浆浓度之比分别为 4.2 和 61.3。总之，结果表明双胍类药物在大鼠肝细胞中的摄取与体内的肝分布一致，口服后苯乙双胍比二甲双胍更有效地被肝脏摄取。
