Perfusion studies of glyburide transfer across the human placenta: implications for fetal safety

Abstract

Objective: Gestational diabetes affects up to 5% of women. Oral hypoglycemics have been avoided because of the assumption that their placental transfer may cause fetal-neonatal hypoglycemia. A recent randomized trial could not show measurable glyburide levels in umbilical blood despite maternal treatment with regular doses of glyburide. The mechanism underlying this phenomenon is not known. The objective of our study was to document, using a human placenta perfusion model, whether glyburide is actively effluxed from the fetal to the maternal circulation.

Study design: In vitro perfusion studies of human cotyledon were performed to quantify placental transfer of glyburide. Using close circle experiments and introducing glyburide to both maternal and fetal circulations at 200 ng/mL, we looked for evidence of transport against concentration gradient from the fetus to the mother. In parallel experiments, the P-glycoprotein inhibitor verapamil was used in an attempt to inhibit transplacental glyburide movement.

Results: There was highly significant transfer of glyburide against concentration gradient from the fetal to the maternal circulation. Fetal-to-maternal concentration ratio was 0.92 +/- 0.23 at the start of the experimental period and 0.31 +/- 0.47 3 hours later (P = .01) (n = 5). Verapamil did not modify glyburide transport.

Conclusion: This is the first direct evidence of active glyburide transport from the fetus to the mother and, in general, of any medicinal drug used during pregnancy. These experiments suggest that glyburide is actively efflux by a transporter other than P-glycoprotein. Alternatively, it is possible that a minority of glyburide is carried by P-glycoprotein, but most of the fetal load is pumped to the mother by a yet-unidentified placental transport system.