• Publikační typ
• abstrakt z konference MeSH

• Publikační typ
• abstrakt z konference MeSH

Inhibition of cyclin-dependent kinases by specific small molecules, purine cyclin-dependent kinase inhibitors (CDKi), has become a promising strategy for cancer treatment. Although pharmacodynamic properties of these compounds have been studied extensively, their pharmacokinetic behavior has not been addressed in detail. In this study, we investigated possible inhibitory effect of five purine CDKi on breast cancer resistance protein (ABCG2) transport activity employing in vitro transport and accumulation methods in MCDKII cells transduced with human ABCG2. Hoechst 33342 and glyburide were used as model ABCG2 substrates for these experiments. In addition, in situ method of dually perfused rat term placenta was utilized to confirm our in vitro results at the organ level. Fumitremorgin C was used as a model inhibitor of ABCG2 for comparison purposes. We demonstrate significant inhibition of ABCG2 by four of the five CDKi tested. Regarding their ABCG2-inhibitory potencies, the investigated compounds can be ranked as follows: purvalanol A>olomoucine II≈fumitremorgin C>roscovitine≈bohemine, with slight differences among substrates, concentrations and methods used. Based on our findings, it is reasonable to expect a substantial impact of the studied CDKi on the pharmacokinetic and pharmacodynamic behavior of concomitantly administered ABCG2 substrates. Moreover, using combination index method of Chou-Talalay, we confirmed that the strongest inhibitors, purvalanol A and olomoucine II, can synergistically potentiate cytostatic effect of mitoxantrone, an ABCG2 substrate, in ABCG2 expressing cell lines.

• MeSH
• ABC transportéry antagonisté a inhibitory   metabolismus   MeSH
• antitumorózní látky farmakologie   MeSH
• benzimidazoly metabolismus   MeSH
• buněčné linie MeSH
• chemorezistence účinky léků   MeSH
• cyklin-dependentní kinasy antagonisté a inhibitory   MeSH
• cytostatické látky farmakologie   MeSH
• glibenklamid metabolismus   MeSH
• lidé MeSH
• mitoxantron farmakologie   MeSH
• nádorové proteiny antagonisté a inhibitory   metabolismus   MeSH
• nádory prsu farmakoterapie   MeSH
• puriny farmakologie   MeSH
• synergismus léků MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

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

Breast cancer resistance protein (BCRP/ABCG2) is a member of the ATP-binding cassette transporter family that recognizes a variety of chemically unrelated compounds. Its expression has been revealed in many mammal tissues, including placenta. The purpose of this study was to describe its role in transplacental pharmacokinetics using rat placental HRP-1 cell line and dually perfused rat placenta. In HRP-1 cells, expression of Bcrp, but not P-glycoprotein, was revealed at mRNA and protein levels. Cell accumulation studies confirmed Bcrp-dependent uptake of BODIPY FL prazosin. In the placental perfusion studies, a pharmacokinetic model was applied to distinguish between passive and Bcrp-mediated transplacental passage of cimetidine as a model substrate. Bcrp was shown to act in a concentration-dependent manner and to hinder maternal-to-fetal transport of the drug. Fetal-to-maternal clearance of cimetidine was found to be 25 times higher than that in the opposite direction; this asymmetry was partly eliminated by BCRP inhibitors fumitremorgin C (2 microM) or N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918; 2 microM) and abolished at high cimetidine concentrations (1000 microM). When fetal perfusate was recirculated, Bcrp was found to actively remove cimetidine from the fetal compartment to the maternal compartment even against a concentration gradient and to establish a 2-fold maternal-to-fetal concentration ratio. Based on our results, we propose a two-level defensive role of Bcrp in the rat placenta in which the transporter 1) reduces passage of its substrates from mother to fetus but also 2) removes the drug already present in the fetal circulation.

• MeSH
• ABC transportéry analýza   fyziologie   genetika   MeSH
• buněčné linie MeSH
• cimetidin farmakokinetika   MeSH
• financování organizované MeSH
• imunohistochemie MeSH
• krysa rodu rattus MeSH
• messenger RNA analýza   MeSH
• metabolická clearance MeSH
• P-glykoprotein fyziologie   MeSH
• perfuze MeSH
• placenta metabolismus   MeSH
• potkani Wistar MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH