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

• Text
• PDF

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