PT  - JOURNAL ARTICLE
AU  - De-Sheng Wang
AU  - Hiroyuki Kusuhara
AU  - Yukio Kato
AU  - Johan W. Jonker
AU  - Alfred H. Schinkel
AU  - Yuichi Sugiyama
TI  - Involvement of Organic Cation Transporter 1 in the Lactic Acidosis Caused by Metformin
AID  - 10.1124/mol.63.4.844
DP  - 2003 Apr 01
TA  - Molecular Pharmacology
PG  - 844--848
VI  - 63
IP  - 4
4099  - http://molpharm.aspetjournals.org/content/63/4/844.short
4100  - http://molpharm.aspetjournals.org/content/63/4/844.full
SO  - Mol Pharmacol2003 Apr 01; 63
AB  - 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. When mice were given metformin, the blood lactate concentration significantly increased in the wild-type mice, whereas only a slight increase was observed in Oct1(−/−) mice. The plasma concentration of metformin exhibited similar time profiles between the wild-type and Oct1(−/−) mice, suggesting that the liver is the key organ responsible for the lactic acidosis. Furthermore, the extent of the increase in blood lactate caused by three different biguanides (metformin, buformin, and phenformin) was compared with the abilities to reduce oxygen consumption in isolated rat hepatocytes. When rats were given each of these biguanides, the lactate concentration increased significantly. This effect was dose-dependent, and the EC50 values of metformin, buformin, and phenformin were 734, 119, and 4.97 μM, 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 μmol/min/mg protein) was compared with the EC50 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. The American Society for Pharmacology and Experimental Therapeutics