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

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-transp orting P-gp in toxicological protection of the fetus, we used mice with a t argeted 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 singl e mother. Intravenous administration of the P-gp substrate drugs [H-3]digox in, [C-14]saquinavir, or paclitaxel to pregnant dams revealed that 2.4-, 7- , or 16-fold more drug, respectively, entered the Mdr1a(-/-)/1b(-/-) fetuse s than entered wild-type fetuses. Furthermore, placental P-gp activity coul d be completely inhibited by oral administration of the P-gp blockers PSC83 3 or GG918 to heterozygous mothers. Our findings imply that the placental d rug-transporting P-gp is of great importance in limiting the fetal penetrat ion of various potentially harmful or therapeutic compounds and demonstrate that this P-gp function can be abolished by pharmacological means. The lat ter principle could be applied clinically to improve pharmacotherapy of the unborn child.