The medical treatment of pregnant women, as well as their fetuses, has become a common clinical practice in developed countries. Therefore, detailed knowledge of maternofetal pharmacokinetics, including the role of drug-efflux transporters in the fetoplacental unit, is crucial to optimize drug choice and dosage schemes and to avoid or exploit possible drug-drug interactions on placental transporters in order to assure appropriate drug levels in the mother and/or fetus. Breast cancer resistance protein (BCRP, ABCG2) is the most recent member of ATP-binding cassette drug-efflux transporters that has been associated with resistance in cancer chemotherapy. Importantly, ABCG2 has also been localized in various normal tissues, affecting the pharmacokinetics of several xenobiotics as well as a number of physiological substances. Extensive expression of ABCG2 in tissue barriers, such as the blood-brain barrier, intestine, testis, or placenta, suggests that ABCG2 plays an important role in the protection of sensitive tissues against toxins. In the placenta, ABCG2 has been experimentally evidenced to actively pump its substrates in the fetal-to-maternal direction and to play an important role in transplacental pharmacokinetics, fetal protection, and detoxication. Further, ABCG2 expression in embryonic and fetal membranes over the course of pregnancy helps ensure proper function of the fetoplacental unit. In this review, we summarize the current knowledge regarding expression and function of ABCG2 in the fetoplacental unit during the development of the fetus and overview the aspects of transplacental pharmacokinetics, ABCG2 regulation, and clinical significance of the transporter for pharmacotherapy in pregnancy.
- MeSH
- ABC transportéry genetika metabolismus MeSH
- embryo savčí fyziologie MeSH
- klinické zkoušky jako téma MeSH
- lidé MeSH
- nádorové proteiny genetika metabolismus MeSH
- placenta metabolismus MeSH
- plod fyziologie MeSH
- polymorfismus genetický MeSH
- těhotenství fyziologie MeSH
- tkáňová distribuce MeSH
- xenobiotika metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- těhotenství fyziologie MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) are the most abundantly expressed ATP-binding cassette (ABC) drug transporters in the placenta. They recognize a large, partly overlapping spectrum of chemically unrelated compounds and affect their transplacental passage. In this study we investigate the effect of Bcrp and P-gp on the transplacental pharmacokinetics of their specific and common substrates employing the technique of dually perfused rat placenta. We show that the clearance of rhodamine 123 (P-gp substrate), glyburide (BCRP substrate) and BODIPY FL prazosin (P-gp and BCRP substrate) in fetal-to-maternal direction is 11, 11.2 and 4 times higher, respectively, than that in the maternal-to-fetal direction. In addition, all of these substances were found to be transported from the fetal compartment even against concentration gradient. We thus demonstrate the ability of placental ABC transporters to hinder maternal-to-fetal and accelerate fetal-to-maternal transport in a concentration-dependent manner. However, by means of pharmacokinetic modeling we describe the inverse correlation between lipid solubility of a molecule and its active transport by placental ABC efflux transporters. Therefore, in the case of highly lipophilic substrates, such as BODIPY FL prazosin in this study, the efficacy of efflux transporters to pump the molecule back to the maternal circulation is markedly limited.
- MeSH
- ABC transportéry metabolismus MeSH
- biologický transport MeSH
- glibenklamid farmakokinetika chemie MeSH
- krysa rodu rattus MeSH
- lipidy chemie MeSH
- maternofetální výměna látek MeSH
- P-glykoprotein metabolismus MeSH
- perfuze MeSH
- placenta metabolismus MeSH
- prazosin analogy a deriváty farmakokinetika chemie MeSH
- rhodamin 123 farmakokinetika chemie MeSH
- rozpustnost MeSH
- sloučeniny boru farmakokinetika chemie MeSH
- substrátová specifita MeSH
- techniky in vitro MeSH
- těhotenství MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
- MeSH
- ABC transportéry farmakologie účinky léků MeSH
- financování organizované MeSH
- geny BRCA1 účinky léků MeSH
- geny BRCA2 účinky léků MeSH
- indeny antagonisté a inhibitory diagnostické užití MeSH
- krysa rodu rattus MeSH
- metabolická inaktivace fyziologie MeSH
- modely u zvířat MeSH
- P-glykoprotein genetika účinky léků MeSH
- placenta fyziologie účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- abstrakty MeSH
Breast cancer resistance protein (BCRP/ABCG2) is an ABC family drug efflux transporter expressed in a number of physiological tissues including placenta. Here we investigated the expression and function of Bcrp in the rat placenta and fetus during pregnancy. We show that the expression of Bcrp mRNA in placenta peaks on gestation day (gd) 15 and declines significantly to one third up to term. In fetal body tissue, 6.9 and 7.4-fold Bcrp mRNA increase was detected on gds 15 and 18, respectively, compared to the early gd 12. The expression of Bcrp mRNA in fetal organs on gds 18 and 21 is also demonstrated. Additionally, the function of placental and fetal Bcrp during pregnancy was studied by fetal exposure to cimetidine infused to the maternal circulation. The relative amount of drug that penetrated to fetus was highest on gd 12 and decreased to one tenth thereafter. Studies on cimetidine distribution in fetus revealed 2- and 4.4-times lower penetration to the brain on gds 18 and 21, respectively, compared to the whole fetal tissue. Our results indicate that the rat fetus is protected by Bcrp against potentially detrimental substances from gd 15 onwards. Moreover, we propose that the protection of fetus by placental Bcrp is further strengthened by fetal Bcrp.
- MeSH
- ABC transportéry genetika MeSH
- cimetidin farmakokinetika krev MeSH
- financování organizované MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- matka - expozice noxám MeSH
- messenger RNA metabolismus MeSH
- placenta metabolismus účinky léků MeSH
- plod metabolismus účinky léků MeSH
- potkani Wistar MeSH
- protivředové látky farmakokinetika krev MeSH
- těhotenství MeSH
- tkáňová distribuce MeSH
- vývojová regulace genové exprese fyziologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH