The Organic Cation Transporter 3 (OCT3) Facilitates Fetal Disposition of Metformin during Pregnancy

Abstract

Metformin used in the treatment of gestational diabetes is transported by multiple organic cation transporters. Metformin crosses the placental barrier, but the underlying transport mechanisms are unknown. The goal of this study was to determine the role of organic cation transporter 3 (OCT3) in metformin transport across the placenta. The expression of OCT3 and other organic cation transporters were quantified in mouse and human placentas by real‐time PCR. The membrane localization of OCT3 in human term placenta was determined by immunofluorescence microscopy. Finally, the in vivo impact of Oct3 in fetal disposition of metformin was investigated in pregnant wild type and Oct3 knockout mice. Our results showed that both human and mouse placentas predominantly express OCT3 with minimal expression of OCT1/2, MATE1/2 and PMAT. OCT3 protein was localized to the basal membrane of syncytiotrophoblasts facing the fetus. After oral dosing of [14C] metformin, the overall drug exposure (AUC0–480 min) in maternal plasma was comparable between wild type and Oct3−/− pregnant mice. However, fetal AUC0–480 min of metformin in Oct3−/− pregnant mice was about 40% less than that in the wild type pregnant mice. These results suggest that OCT3 mediates transport of metformin from the placental cells into the fetus and plays an important role in the transport of metformin and other organic cations at the maternal‐fetal interface.