Liver uptake of Biguanides in rats

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 Km values for metformin and phenformin were 404 and 5.17 μM, respectively, with CLint (Vmax/Km) values 1.58 μl/min per 106 cells and 34.7 μl/min per 106 cells. In in vivo experiments, when 14C-metformin and 14C-phenformin were given orally to male rats at a dose of 50 mg/kg, the liver concentrations of radioactivity at 0.5 hour after dosing were 21.5 μg eq./g with metformin but 147.1 μg 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.