Transport of biguanides by human organic cation transporter OCT2

Abstract Biguanides have the severe side effect of lactic acidosis. Although both metformin and phenformin are biguanide derivatives, there is a difference in the frequency at which they induce lactic acidosis. However, the reasons for the difference are not clear. Metformin has been reported to be mainly excreted into urine by human organic cation transporter 2 (hOCT2). The present study was designed to investigate the renal transport of metformin and phenformin, focusing on hOCT2, using hOCT2–expressing oocytes. Both biguanides were found to be good substrates for hOCT2. However, phenformin exhibited a higher affinity and transport activity than metformin. The K m values for metformin and phenformin were 235 and 37.4 μM, with CL int (V max /K m ) values of 71.9 × 10 −3  μL/min per oocyte and 209 × 10 −3  μL/min per oocyte, respectively. This is the first report that has compared the transport profiles of these biguanides in hOCT2–expressing oocytes. The results suggest that plasma concentration of phenformin in subjects carrying hOCT2 variant may be higher compared to reference subjects, as reported in metformin. In addition, the relationship between plasma concentration of these biguanides and blood lactate level as well as the possible reasons for the difference in the associated frequency of occurrence of lactic acidosis are discussed.