49: Multiple ABC transporters of human placental brush border membranes contribute to the efflux of glyburide, rosiglitazone, and metformin


      The combined use of hypoglycemic drugs Glucovance (glyburide + metformin) and rosiglitazone has been evaluated in nonpregnant patients with type 2 diabetes mellitus. However, the role of the placenta in the biodisposition of a combination of oral hypoglycemic drugs during pregnancy remains unclear. Previous reports from our laboratory demonstrated that multiple drugs could compete for efflux by P-glycoprotein (P-gp). Therefore, co-administration of hypoglycemic drugs which are substrates of placental efflux transporters could introduce competition for a single efflux transporter thus increasing their transfer to the fetal circulation. The aim of this investigation was to identify the major human placental ABC transporters responsible for the efflux of glyburide, rosiglitazone, and metformin.

      Study Design

      Inside-out brush border membrane vesicles (BBMVs) were prepared from trophoblast tissue of 60 term placentas obtained from healthy pregnancies. Chemical inhibitors selective for each of the ABC transporters P-gp, Breast Cancer Resistance Protein (BCRP), and Multidrug Resistance Protein 1 (MRP1) were used to inhibit the ATP-dependent uptake of [3H]-glyburide, [3H]-rosigitazone, or [14C]-metformin by BBMVs.


      The three transporters contributed to 78 ± 4 % of total glyburide efflux in placental BBMVs. The contributions of each transporter to the total efflux were MRP1 (43 ± 4%); BCRP (25 ± 5%); and P-gp (9 ± 5%). P-gp was responsible for 73 ± 1% of rosiglitazone efflux, with minimal contributions by BCRP and MRP1. ABC transporters extruded ∼80% of metformin with 58 ± 20% achieved by P-gp and 25 ± 14% by BCRP.


      The placental ABC transporters investigated each contribute to the efflux of glyburide, rosiglitazone, and metformin to a different extent. If multiple drugs are co-administered, the major transporter responsible for the extrusion of one could be a site of competition for efflux, thus leading to an increase in drug concentration in the fetal circulation. Supported by OPRU.