Absence or pharmacological blocking of placental P-glycoprotein profoundly increases fetal drug exposure
AUTOR(ES)
Smit, Johan W.
FONTE
American Society for Clinical Investigation
RESUMO
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.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=409845Documentos Relacionados
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