Functional role of P-glycoprotein in the human blood-placental barrier
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and PathologyDepartment of Medical Sciences2005 (English)In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 78, no 2, 123-31 p.Article in journal (Refereed) Published
OBJECTIVE: In vitro and animal experiments suggest that P-glycoprotein forms a functional barrier between maternal and fetal blood circulation in the placenta, thus protecting the fetus from exposure to xenobiotics during pregnancy. In this study we aimed to characterize the role of P-glycoprotein in the blood-placental barrier by use of dually perfused human placenta. METHODS: Twenty-eight human placentas were obtained after delivery, and both the maternal side and the fetal side were perfused for 2 hours. Saquinavir was used as a probe drug for P-glycoprotein-dependent active transfer, and PSC833 (valspodar) or GG918 was used as an inhibitor of P-glycoprotein function in a maternal-to-fetal and fetal-to-maternal perfusion setting. Genotyping for ABCB1 (C3435T and G2677A/T) polymorphism and quantification of P-glycoprotein expression were done for each placenta. RESULTS: The fetal-to-maternal transfer of saquinavir was 108-fold higher (P = .003) compared with transfer from the maternal to the fetal direction. Preperfusion with PSC833 increased the placental transfer of saquinavir by 7.9-fold (P < .001), and preperfusion with GG918 increased it by 6.2-fold (P < .001). The end-perfusion transfer (percentage) of saquinavir at 120 minutes was 11-fold (P < .001) and 6-fold (P < .001) higher in placentas preperfused with PSC833 and GG918, respectively, compared with control. However, PSC833 had no effect on the transfer of saquinavir from the fetal to the maternal direction (P = .79). P-glycoprotein expression was correlated with the PSC833-induced change in the saquinavir transfer (r = 0.75, P = .086). ABCB1 polymorphism did not affect the PSC833- or GG918-induced change in the saquinavir transfer. CONCLUSIONS: P-glycoprotein has a major functional role in the human blood-placental barrier but a negligible role in the removal of substances from the fetal circulation to maternal blood. Pharmacologic blockade of P-glycoprotein function can lead to disruption of the blood-placental barrier and increase the transfer of P-glycoprotein substrates to the fetal side by several-fold, which may be a noteworthy mechanism for teratogenicity.
Place, publisher, year, edition, pages
2005. Vol. 78, no 2, 123-31 p.
Acridines/pharmacology, Cyclosporins/pharmacology, Female, HIV Protease Inhibitors/blood/*pharmacokinetics, Humans, Maternal-Fetal Exchange, P-Glycoprotein/*metabolism, Placenta/*metabolism, Pregnancy, Saquinavir/blood/*pharmacokinetics, Tetrahydroisoquinolines/pharmacology
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-74343DOI: 10.1016/j.clpt.2005.04.014PubMedID: 16084847OAI: oai:DiVA.org:uu-74343DiVA: diva2:102253