Absence or pharmacological blocking of placental P-glycoprotein profoundly increases 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-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 [(3)H]digoxin, [(14)C]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.
Smit
J W
JW
Division of Experimental Therapy, The Netherlands Cancer Institute, 1066 CX Amsterdam.
Huisman
M T
MT
van Tellingen
O
O
Wiltshire
H R
HR
Schinkel
A H
AH
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D002250:Carbon Radioisotopes; D003433:Crosses, Genetic; D004077:Digoxin / Q000493:pharmacokinetics; D005260:Female; D006579:Heterozygote; D007306:Insecticides / Q000633:toxicity*; D007559:Ivermectin / Q000031:analogs & derivatives* / Q000633:toxicity; D008297:Male; D008431:Maternal-Fetal Exchange; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D017239:Paclitaxel / Q000493:pharmacokinetics; D010920:Placenta / Q000502:physiology*; D011247:Pregnancy; D019258:Saquinavir / Q000493:pharmacokinetics; D014018:Tissue Distribution
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002250:Carbon Radioisotopes; D007306:Insecticides; D007559:Ivermectin; C019264:avermectin; D004077:Digoxin; D019258:Saquinavir; D017239:Paclitaxel