Kakemi M, Sasaki H, Saeki K, Endoh M, Katayama K, Koizumi T
J Pharmacobiodyn. 1983 Feb;6(2):71-87. doi: 10.1248/bpb1978.6.71.
The purpose of this investigation is to elucidate the relationship between the time course of pharmacologic effects and drug disposition after administration of metformin, an oral antidiabetic drug of biguanides. Alloxan diabetic rats and normal rats were used in the experiments. After administration of metformin, plasma glucose levels, blood pyruvate levels, blood lactate levels, plasma pancreatic glucagon immunoreactivity (pancreatic GI) and plasma gut glucagon like immunoreactivity (gut GLI) were determined as well as serum concentrations of metformin. In alloxan diabetic rats, gut GLI levels were significantly correlated to the logarithm of tissue metformin levels, calculated from serum metformin levels. The blood lactate, pyruvate and plasma glucose levels were also linearly related to gut GLI levels, after metformin administration. It was also clarified that metformin did not inhibit the intestinal absorption of glucose and that metformin presumably inhibited the hepatic gluconeogenesis. It is reasonable to consider that the effect of metformin on the gut GLI level is the primal effect, and that other pharmacologic effects such as plasma glucose lowering, blood lactate and pyruvate increasing effects are the consequences of the primal effect, at least in alloxan diabetic rats. While in normal rats, plasma gut GLI levels were not significantly related to metformin tissue levels, however, plasma glucose levels were considerably correlated with the logarithm of the plasma or tissue metformin levels. These results indicated that the effect of gut GLI was entirely masked by endogeneous insulin, which might be secreted by metformin administration.
本研究的目的是阐明口服双胍类降糖药二甲双胍给药后药理效应的时程与药物处置之间的关系。实验采用四氧嘧啶糖尿病大鼠和正常大鼠。给予二甲双胍后，测定血浆葡萄糖水平、血丙酮酸水平、血乳酸水平、血浆胰高血糖素免疫反应性（胰腺GI）和血浆肠胰高血糖素样免疫反应性（肠GLI）以及二甲双胍的血清浓度。在四氧嘧啶糖尿病大鼠中，肠GLI水平与根据血清二甲双胍水平计算的组织二甲双胍水平的对数显著相关。给予二甲双胍后，血乳酸、丙酮酸和血浆葡萄糖水平也与肠GLI水平呈线性相关。还阐明了二甲双胍不抑制葡萄糖的肠道吸收，并且二甲双胍可能抑制肝糖异生。有理由认为，二甲双胍对肠GLI水平的影响是主要作用，而其他药理作用如降低血浆葡萄糖、增加血乳酸和丙酮酸的作用是该主要作用的结果，至少在四氧嘧啶糖尿病大鼠中是如此。而在正常大鼠中，血浆肠GLI水平与二甲双胍组织水平无显著相关性，然而，血浆葡萄糖水平与血浆或组织二甲双胍水平的对数有相当程度的相关性。这些结果表明，肠GLI的作用完全被内源性胰岛素掩盖，内源性胰岛素可能是由二甲双胍给药分泌的。
