General Obstetrics and Gynecology: Obstetrics
Perfusion studies of glyburide transfer across the human placenta: Implications for fetal safety

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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.

Section snippets

In vitro perfusion of placental cotyledon

Placentas were obtained immediately after delivery from elective cesarean sections and were transported to the laboratory in ice-cold heparinized phosphate-buffered saline. Maternal and fetal circulations were established to a peripheral lobule as previously described by our laboratory.11 Perfusion of the placental cotyledon was established within 30 minutes of delivery of the infant.

The perfusate (maintained at 37°C) consisted of a tissue culture medium (M199, Sigma, St. Louis, MO) that

Results

The physical and viability parameters of all perfusion experiments conducted are presented in Table I. The mean (± SD) mass of the perfused cotyledons was 16.6 ± 2 (range 9.8 to 25.7). There was no significant difference in the fetal arterial pressures between the experimental and the control periods (mean ± SD) (Table I). The production of lactate and hCG as well as the rate of consumption of glucose and oxygen did not vary between the experimental and the control periods. There was no

Comment

This study provides the first evidence of transplacental efflux against a concentration gradient of glyburide from the fetal to the maternal circulation in humans. It is also the first evidence of active efflux of any medicinal drug used in human pregnancy.

In 1994 Elliott et al,14 using a similar model, showed that significantly less glyburide introduced in the maternal circulation finds itself into the fetal circulation, as compared with other oral hypoglycemics (eg, chlorpropamide,

References (16)

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Supported by a grant from the Canadian Institute for Health Research. G.K. is holder of the Ivey Chair in Molecular Toxicology at the University of Western Ontario and the Research Leadership in Better Pharmacotherapy During Pregnancy and Lactation at the Hospital for Sick Children.

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