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Absence or pharmacological blocking of placental P-glycoprotein profoundly increases fetal drug exposure
Johan W. Smit, … , Hugh R. Wiltshire, Alfred H. Schinkel
Johan W. Smit, … , Hugh R. Wiltshire, Alfred H. Schinkel
Published November 15, 1999
Citation Information: J Clin Invest. 1999;104(10):1441-1447. https://doi.org/10.1172/JCI7963.
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Article

Absence or pharmacological blocking of placental P-glycoprotein profoundly increases fetal drug exposure

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Abstract

It was recently shown that naturally occurring Mdr1a mutant fetuses of the CF-1 outbred mouse stock have no placental Mdr1a P-glycoprotein (P-gp) and that this absence is associated with increased sensitivity to avermectin, a teratogenic pesticide. To further define the role of placental drug-transporting P-gp in toxicological protection of the fetus, we used mice with a targeted disruption of the Mdr1a and Mdr1b genes. Mdr1a+/–/1b+/– females were mated with Mdr1a+/–/1b+/– males to obtain fetuses of 3 genotypes (Mdr1a+/+/1b+/+, Mdr1a+/–/1b+/–, and Mdr 1a–/–/1b–/–) in a single mother. Intravenous administration of the P-gp substrate drugs [3H]digoxin, [14C]saquinavir, or paclitaxel to pregnant dams revealed that 2.4-, 7-, or 16-fold more drug, respectively, entered the Mdr1a–/–/1b–/– fetuses than entered wild-type fetuses. Furthermore, placental P-gp activity could be completely inhibited by oral administration of the P-gp blockers PSC833 or GG918 to heterozygous mothers. Our findings imply that the placental drug-transporting P-gp is of great importance in limiting the fetal penetration of various potentially harmful or therapeutic compounds and demonstrate that this P-gp function can be abolished by pharmacological means. The latter principle could be applied clinically to improve pharmacotherapy of the unborn child.

Authors

Johan W. Smit, Maarten T. Huisman, Olaf van Tellingen, Hugh R. Wiltshire, Alfred H. Schinkel

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Figure 2

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Ratio of [14C]saquinavir fetal concentration to maternal plasma concentr...
Ratio of [14C]saquinavir fetal concentration to maternal plasma concentration. Heterozygous mice were mated, and [14C]saquinavir (1 mg/kg) was administered intravenously to pregnant dams at gestation day 15. At 5 or15 minutes after dosing, dams were euthanized, and fetuses from 4 litters were collected. Maternal plasma and fetal drug content and genotypes were determined as described in Methods. Open bars indicate wild-type values, hatched bars heterozygous values, and black bars Mdr1a–/–/1b–/– values. Values are expressed as mean [14C]saquinavir concentration in fetal tissues normalized to maternal plasma [14C]saquinavir concentration. Four to 27 fetuses of each genotype were analyzed. Average maternal plasma concentration was 429 ± 32 ng/mL and 145.9 ± 16 ng/mL at 5 minutes and 15 minutes after [14C]saquinavir administration, respectively. All animals had also received oral administration of vehicle 2 hours before intravenous drug administration for proper comparison to PSC833-treated mice (see experiment described in Table 3). Error bars indicate SD. AP < 0.005 vs. wild-type fetuses in pairwise comparison.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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