Involvement of organic cation transporter 2 in the metformin-associated increased lactate levels caused by contrast-induced nephropathy.

The application of iodinated contrast medium has become a risk factor for metformin-associated lactic acidosis (MALA), which leads to the accumulation of metformin in vivo is one of the principal reasons for MALA. However, the molecular mechanism of the adverse event is not yet clear. In this study, iohexol injection was used as a model drug. The contrast agent acute kidney injury rat model, in vivo rat pharmacokinetic study, kidney slices and HK-2 cells were performed to elucidate the pharmacokinetic molecular mechanism of accumulation of metformin caused by contrast-induced nephropathy (CIN). Plasma exposure of metformin was increased significantly in the CIN group compared with that in the normal and control groups. The AUC of metformin was from 2791 ± 382 μg min mL-1 to 4784 ± 767 μg min mL-1. The cumulative urinary excretion of metformin was also reduced in the CIN group. The uptake of metformin decreased in kidney slices in the CIN group. Compared with the normal and control groups, the blood lactate concentration was increased after intravenous administration of metformin in the CIN group followed a similar trend to the plasma concentrations of metformin. After treatment with contrast medium, the expression of OCT2 was reduced in rat kidney and HK-2 cells. These findings highlight that OCT2 deficiency was associated with increased lactate levels during metformin treatment caused by CIN.