PHARMACOLOGIC EFFECTS OF METFORMIN IN RELATION TO ITS DISPOSITION IN ALLOXAN DIABETIC RATS

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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.
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PHARMACOLOGIC EFFECTS OF METFORMIN IN RELATION TO ITS DISPOSITION IN ALLOXAN DIABETIC RATS

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