Research
Basic science: Obstetrics
Role of human placental apical membrane transporters in the efflux of glyburide, rosiglitazone, and metformin

Presented orally at the 30th Annual Meeting of the Society for Maternal-Fetal Medicine, Chicago, IL, Feb. 1-6, 2010.
https://doi.org/10.1016/j.ajog.2010.01.035Get rights and content

Objective

Substrates of placental efflux transporters could compete for a single transporter, which could result in an increase in the transfer of each substrate to the fetal circulation. Our aim was to determine the role of placental transporters in the biodisposition of oral hypoglycemic drugs that could be used as monotherapy or in combination therapy for gestational diabetes.

Study Design

Inside-out brush border membrane vesicles from term placentas were used to determine the efflux of glyburide, rosiglitazone, and metformin by P-glycoprotein, breast cancer resistance protein, and multidrug resistance protein.

Results

Glyburide was transported by multidrug resistance protein (43 ± 4%); breast cancer resistance protein (25 ± 5%); and P-glycoprotein (9 ± 5%). Rosiglitazone was transported predominantly by P-glycoprotein (71 ± 26%). Metformin was transported by P-glycoprotein (58 ± 20%) and breast cancer resistance protein (25 ± 14%).

Conclusion

Multiple placental transporters contribute to efflux of glyburide, rosiglitazone, and metformin. Administration of drug combinations could lead to their competition for efflux transporters.

Section snippets

Chemicals

[3H]-rosiglitazone (specific activity, 50 Ci/mmol) and [14C]-metformin (specific activity, 50 mCi/mmol) were purchased from American Radiolabeled Chemicals, Inc (St. Louis, MO), and [3H]-glyburide (specific activity, 44.6 Ci/ mmol) from Perkin-Elmer (Boston, MA). All other chemicals were purchased from Sigma-Aldrich (Dallas, TX) unless otherwise noted.

Clinical material

Placentas from uncomplicated term pregnancies were obtained immediately after vaginal or abdominal deliveries from the labor and delivery ward of

Glyburide transport

The total ATP-dependent uptake of [3H]-glyburide, at its concentration of 100 nM, by placental IOVs was 3.2 ± 0.3 pmol/mg protein × minute. Inhibition of P-gp by verapamil decreased [3H]-glyburide uptake by 9 ± 5%. Inhibition of BCRP by 25 nM KO143 decreased [3H]-glyburide uptake by 25 ± 5%. Inhibition of MRP1 by indomethacin decreased [3H]-glyburide uptake by 43 ± 4%. Total inhibition of P-gp, BCRP, and MRP1 using 1 μM KO143 decreased [3H]-glyburide uptake by 78 ± 4%. The contributions of each

Comment

The goal of this investigation was to better understand the role of human placenta in fetal exposure to hypoglycemic drugs used in the treatment of GDM. To achieve this goal, we determined the activity of placental ABC transporters in the efflux of glyburide, rosiglitazone, and metformin using IOV preparations obtained from placental apical membranes. Because of the reversed orientation of the transporters within the IOVs, transporter uptake of a drug into inverted vesicles represents its

Acknowledgments

We thank the Perinatal Research Division for their assistance and the Publication, Grant, and Media Support of the UTMB Department of Obstetrics and Gynecology.

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    Reprints not available from the authors.

    Supported by the Obstetric-Fetal Pharmacology Research Unit (OPRU) Network (no. U10H0047891).

    Cite this article as: Hemauer SJ, Patrikeeva SL, Nanovskaya TN, et al. Role of human placental apical membrane transporters in the efflux of glyburide, rosiglitazone, and metformin. Am J Obstet Gynecol 2010;202:383.e1-7.

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