# Absence of Metformin in Fetal Circulation Following Maternal Administration in Late Gestation Pregnant Sheep

## TL;DR

This study shows that metformin given to pregnant sheep does not reach the fetus, unlike in humans, due to differences in placental structure.

## Contribution

The study reveals that the ovine placenta is impermeable to metformin, offering new insights into species-specific placental transport mechanisms.

## Key findings

- Maternal metformin administration in sheep did not result in fetal metformin exposure.
- OCT1 transporter expression in placental tissues was very low compared to the fetal liver.
- Anatomical differences in the ovine placenta likely prevent metformin transport to the fetus.

## Abstract

In human pregnancy, metformin administered to the mother crosses the placenta resulting in metformin exposure to the fetus. However, the effects of metformin exposure on the fetus are poorly understood and difficult to study in humans. Pregnant sheep are a powerful large animal model for studying fetal physiology. The objective of this study was to determine if maternally administered metformin at human dose-equivalent concentrations crosses the ovine placenta and equilibrates in the fetal circulation. To test this, metformin was administered to the pregnant ewe via continuous intravenous infusion or supplementation in the drinking water. Both administration routes increased maternal metformin concentrations to human dose-equivalent concentrations of ~ 10 µM, yet metformin was negligible in the fetus even after 3–4 days of maternal administration. In cotyledon and caruncle tissue, expression levels of the major metformin uptake transporter organic cation transporter 1 (OCT1) were < 1% of expression levels in the fetal liver, a tissue with abundant expression. Expression of other putative uptake transporters OCT2 and OCT3, and efflux transporters multidrug and toxin extrusion (MATE)1 and MATE2were more abundant. These results demonstrate that the ovine placenta is impermeable to maternal metformin administration. This is likely due to anatomical differences and increased interhaemal distance between the maternal and umbilical circulations in the ovine versus human placenta limiting placental metformin transport.