Molecular pharmacology
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Molecular pharmacology · Apr 2003
Involvement of organic cation transporter 1 in the lactic acidosis caused by metformin.
Biguanides are a class of drugs widely used as oral antihyperglycemic agents for the treatment of type 2 diabetes mellitus, but they are associated with lactic acidosis, a lethal side effect. We reported previously that biguanides are good substrates of rat organic cation transporter 1 (Oct1; Slc22a1) and, using Oct1(-/-) mice, that mouse Oct1 is responsible for the hepatic uptake of a biguanide, metformin. In the present study, we investigated whether the liver is the key organ for the lactic acidosis. ⋯ This effect was dose-dependent, and the EC(50) values of metformin, buformin, and phenformin were 734, 119, and 4.97 microM, respectively. All of these biguanides reduced the oxygen consumption by isolated rat hepatocytes in a concentration-dependent manner. When the concentration required to reduce the oxygen consumption to 75% of the control value (from 0.40 to 0.29 micromol/min/mg protein) was compared with the EC(50) value obtained in vivo, a clear correlation was observed among the three biguanides, suggesting that oxygen consumption in isolated rat hepatocytes can be used as an index of the incidence of lactic acidosis.