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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-gp, Breast Cancer Resistance Protein (BCRP), and Multidrug Resistance Protein (MRP1).Results-Glyburide was transported by MRP1 (43 ± 4%); BCRP (25 ± 5%); and P-gp (9 ± 5%). Rosiglitazone was transported predominantly by P-gp (71 ± 26%). Metformin was transported by Pgp (58 ± 20%) and BCRP (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.

Objectives Determine the bidirectional transfer of pravastatin across the dually perfused term human placental lobule and its distribution between the tissue, maternal and fetal circuits. Study design The transfer of pravastatin was determined in the Maternal-to-Fetal (n=11) and Fetal-to-Maternal (n=10) directions. Pravastatin was co-perfused with its [3H]-isotope and the marker compound antipyrine (20 μg/mL) and its [14C]-isotope. The concentration of pravastatin in the perfused tissue, the maternal and fetal circuits was determined using liquid scintillation spectrometry. Inside-out vesicles prepared from placental brush border membranes were utilized to investigate the role of efflux transporters in transplacental transfer of pravastatin. Results Pravastatin was transferred from the maternal to the fetal circuit and vise versa. In the Maternal-to-Fetal direction, the distribution of pravastatin at the end of experiment was as follows: 14 ± 5% of the drug was retained by the tissue, 68 ± 5% remained in the maternal circuit, and 18±4% was transferred to the fetal circuit. The normalized transfer of pravastatin (Clearance index) to antipyrine in the Fetal-to-Maternal direction (0.48 ± 0.07) was higher than its transfer in the Maternal-to-Fetal direction (0.36 ± 0.07, p<0.01). Furthermore, pravastatin inhibited the ATP-dependent uptake of the paclitaxel and estrone sulfate. Conclusions The transfer of pravastatin across the dually perfused placental lobule suggests that fetal exposure to pravastatin is plausible. The higher transfer of pravastatin in the Fetal-to-Maternal direction than the reverse as well as its inhibition of the ATP-dependent uptake of [3H]-paclitaxel and [3H]-estrone sulfate strongly suggest the involvement of efflux transporters in decreasing its transfer across the placenta, and support pravastatin favorable pharmacokinetic profile in pregnancy.

The ABC transporter P-glycoprotein is a product of the MDR1 gene and its function in human placenta is to extrude xenobiotics from the tissue thus decreasing fetal exposure. The goal of this investigation was to examine the effect of three polymorphisms in the MDR1 gene on the expression and activity of placental P-gp. In 199 term placentas examined, the C1236T variant was associated with 11% lower P-gp protein expression than wild type, while the C3435T and G2677T/A variants each were associated with a 16% reduction (p < 0.05). Homozygotes for the C1236T and C3435T variant allele (TT) were associated with 42% and 47% increase in placental P-gp transport activity, respectively (p = 0.04 and p = 0.02) of the prototypic substrate, [ 3 H]-paclitaxel. These findings indicate that the C3435T and G2677T/A SNPs in MDR1 are significantly associated with decreased placental P-gp protein expression, while the C1236T and C3245T homozygous variants are significantly associated with an increase in its efflux activity.