The placenta is the first organ to be created during mammalian development. As the main link between the mother and the fetus it has more diverse functions than any other organ, serving as a digestive, excretory, respiratory, endocrine, and immune system. The outer layer of the placenta, the trophoblast, plays a key role in fetal development by orchestrating all these functions. Recent research has associated perturbations of maternal conditions (such as malnutrition, stress or inflammation) with alterations of the trophoblasts' endocrine, transport and metabolic processes. As reviewed here, adaptations to these conditions enable the fetus to survive, but at the cost of permanently changing its physiology and structure. Moreover, these adaptations trigger fetal programming that increases predisposition to various pathological conditions in adult life, typically metabolic, cardiovascular or CNS diseases.

• Klíčová slova
• Fetal development, Fetal programming, Placenta, Pregnancy, Trophoblast,
• MeSH
• biologické modely MeSH
• lidé MeSH
• maternofetální výměna látek účinky léků   fyziologie   MeSH
• placenta fyziologie   MeSH
• těhotenství MeSH
• trofoblasty cytologie   účinky léků   fyziologie   MeSH
• vývoj plodu účinky léků   fyziologie   MeSH
• xenobiotika toxicita   MeSH
• zpožděný efekt prenatální expozice etiologie   patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• xenobiotika MeSH

INTRODUCTION: Medication of pregnant women is increasingly common in developed countries. Several placental drug transporters have been shown to transfer their substrates from the trophoblast back to the maternal circulation, thus hindering the transplacental passage of xenobiotics and protecting the fetus. However, the expression and activity of drug transporter proteins in the placenta vary during gestation and are tightly regulated by many factors. In addition, their function can be compromised by pathological conditions and/or drug-drug interactions. AREAS COVERED: This article reviews current knowledge on placental drug transporters, their effects on placental pharmacokinetics and the regulatory mechanisms that control their expression and activity. Transcriptional, genetic and epigenetic mechanisms of placental transporter regulation and the drug-drug interactions that modulate transporter activity are described. Physiological and pathological factors that can affect drug transporter expression and function in the placenta are also discussed. EXPERT OPINION: The expression and activity of drug transporter proteins in the placenta vary during gestation and are tightly regulated by many factors. Subsequently, there is a great variability in the expression and function of placental drug transporters both within human populations (interindividual variability) and also during gestation (intraindividual variability). An understanding of the expression and function of placental drug transporters is essential for efficient and safe therapy during pregnancy. There is clearly a need for further preclinical and clinical studies on placental drug transporters, but such investigations must be carefully designed and the resulting data should be evaluated with great caution. This review highlights several methodological aspects that will have to be considered and addressed in order to shed further light on these important issues.

• Klíčová slova
• drug transporter, epigenetics, expression, genetics, gestation, pharmacokinetics, pharmacotherapy, placenta, pregnancy, regulation,
• MeSH
• biologický transport fyziologie   MeSH
• lékové interakce MeSH
• lidé MeSH
• maternofetální výměna látek fyziologie   MeSH
• membránové transportní proteiny genetika   metabolismus   MeSH
• placenta metabolismus   MeSH
• těhotenství MeSH
• xenobiotika škodlivé účinky   farmakokinetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• membránové transportní proteiny MeSH
• xenobiotika MeSH

Pharmacotherapy during pregnancy is often inevitable for medical treatment of the mother, the fetus or both. The knowledge of drug transport across placenta is, therefore, an important topic to bear in mind when deciding treatment in pregnant women. Several drug transporters of the ABC and SLC families have been discovered in the placenta, such as P-glycoprotein, breast cancer resistance protein, or organic anion/cation transporters. It is thus evident that the passage of drugs across the placenta can no longer be predicted simply on the basis of their physical-chemical properties. Functional expression of placental drug transporters in the trophoblast and the possibility of drug-drug interactions must be considered to optimize pharmacotherapy during pregnancy. In this review we summarize current knowledge on the expression and function of ABC and SLC transporters in the trophoblast. Furthermore, we put this data into context with medical conditions that require maternal and/or fetal treatment during pregnancy, such as gestational diabetes, HIV infection, fetal arrhythmias and epilepsy. Proper understanding of the role of placental transporters should be of great interest not only to clinicians but also to pharmaceutical industry for future drug design and development to control the degree of fetal exposure.

• MeSH
• ABC transportéry metabolismus   MeSH
• biologický transport MeSH
• komplikace těhotenství farmakoterapie   patofyziologie   MeSH
• léčivé přípravky aplikace a dávkování   metabolismus   MeSH
• lékové interakce MeSH
• lidé MeSH
• maternofetální výměna látek fyziologie   MeSH
• membránové transportní proteiny metabolismus   MeSH
• placenta metabolismus   MeSH
• racionální návrh léčiv MeSH
• těhotenství MeSH
• trofoblasty metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• ABC transportéry MeSH
• léčivé přípravky MeSH
• membránové transportní proteiny MeSH

PURPOSE: We followed up lamotrigine transport through the placenta and analyzed maternal and umibilical cord concentrations, its ratio and maternal lamotrigine clearance in monotherapy and in combinations. METHODS: Maternal and umbilical cord concentrations were analyzed during delivery in a cohort of 63 women between 2001 and 2009. The request forms for routine therapeutic drug monitoring were used as the data source. Maternal concentrations were used for the estimation of apparent oral clearance and paired infant and maternal concentrations for estimation of the infant (umibilical cord)/maternal serum concentration ratio. RESULTS: The lamotrigine infant/maternal serum concentration ratio ranged in monotherapy from 0.40 to 1.38 (median 0.91). The ratio in monotherapy showed a possible distribution to two subgroups. Concomitant administration of valproic acid significantly increased both maternal and infant lamotrigine concentrations and significantly decreased lamotrigine clearance by about 65%. Co-medication with carbamazepine increased lamotrigine clearance non-significantly. Highly significant correlations were found between maternal and umbilical cord lamotrigine concentrations, both in monotherapy and in the lamotrigine+valproic acid combination. Infant concentrations of valproic acid were found to be about 30% higher and infant concentrations of carbamazepine were found to be about 20% lower than maternal concentrations. CONCLUSIONS: Our data from the large cohort showed the interindividual variability of umbilical cord/maternal serum concentration ratio in lamotrigine monotherapy caused probably by the different activity of the placental lamotrigine metabolizing enzymes UGT1A4 and 2B7 associated with genetic polymorphism. The potential teratogenic effect of lamotrigine combination with valproic acid could be associated with the higher lamotrigine and valproic acid concentrations in the fetus.

• MeSH
• dospělí MeSH
• epilepsie krev   farmakoterapie   MeSH
• fetální krev metabolismus   MeSH
• kohortové studie MeSH
• lamotrigin MeSH
• lidé MeSH
• maternofetální výměna látek fyziologie   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• novorozenec krev   MeSH
• retrospektivní studie MeSH
• těhotenství krev   MeSH
• triaziny krev   terapeutické užití   MeSH
• vedení porodu * MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• novorozenec krev   MeSH
• těhotenství krev   MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• lamotrigin MeSH
• triaziny MeSH

1. The transplacental transfer of D-xylose was investigated in the present study. 2. Umbilical perfusion of the rat term placenta was used to study materno-foetal (M-F) and foetomaternal (F-M) transfer of this compound. 3. D-Xylose was found to cross the rat term placenta very quickly in the M-F direction, with subsequent accumulation in the foetal compartment (the F-M ratio being 2.23 at the end of the experiments). In contrast, no transfer in the F-M direction was observed. 4. A possible facilitation of the transplacental transfer of D-xylose from the mother to foetus in rats is suggested.

• MeSH
• aktivní transport fyziologie   MeSH
• časové faktory MeSH
• krysa rodu Rattus MeSH
• maternofetální výměna látek fyziologie   MeSH
• perfuze MeSH
• placenta metabolismus   MeSH
• potkani Wistar MeSH
• těhotenství MeSH
• xylosa farmakokinetika   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• xylosa MeSH

There are great interspecies differences in placental structure as well as in permeability properties of the placenta. In all species, however, the placenta behaves like a low-permeability barrier containing specific mechanisms of transcellular transport for minerals and other substrates for fetal growth and metabolism. The minerals that are contained in plasma in low concentrations and that are mainly intracellular or sequestered in bones (K+, Mg2+, Ca2+, phosphate) are transported to the fetus actively. The transfer of the main extracellular ions, Na+ and Cl-, exhibit great interspecies differences. In the sheep, the transfer rates of Na+ and Cl- to the fetus are consistent with passive transfer mechanisms. In the rat, Na+ is transported to the fetus actively and the transfer of Cl- is facilitated by a carrier and/or a channel. Transfer of minerals to the fetus is controlled by a variety of mechanisms ranging from very simple ones depending on intrinsic properties of the transport systems to complex mechanisms of hormonal control. Water is presumed to move across the placenta passively. The transfer may be facilitated by the 28-kDa water channel-forming integral protein (CHIP28), which is expressed in the trophoblast syncytium.

• MeSH
• akvaporin 1 MeSH
• akvaporiny * MeSH
• antigeny krevních skupin MeSH
• chloridy metabolismus   MeSH
• iontové kanály fyziologie   MeSH
• iontový transport fyziologie   MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• maternofetální výměna látek fyziologie   MeSH
• minerály metabolismus   MeSH
• permeabilita MeSH
• placenta metabolismus   fyziologie   ultrastruktura   MeSH
• plod metabolismus   fyziologie   MeSH
• sodík metabolismus   MeSH
• těhotenství MeSH
• voda metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• akvaporin 1 MeSH
• akvaporiny * MeSH
• antigeny krevních skupin MeSH
• AQP1 protein, human MeSH Prohlížeč
• Aqp1 protein, rat MeSH Prohlížeč
• chloridy MeSH
• iontové kanály MeSH
• minerály MeSH
• sodík MeSH
• voda MeSH

OBJECTIVES: We dissected the paracellular and transcellular components of Ca++ transfer across the perfused human placental cotyledon and explored the nature of the transcellular component. STUDY DESIGN: Transfer of 45Ca++ and ethylenediaminetetraacetic acid labeled with chromium 51 was measured across the in vitro perfused cotyledon of the human placenta, and paracellular and transcellular components of the transfer of Ca++ were calculated from the transfer of the two tracers. RESULTS: The transcellular component of the Ca++ transfer in the maternal-fetal direction represented about one third of the total maternal-fetal transfer. It was saturable, sensitive to cyanide, and insensitive to verapamil. The transcellular component in the fetal-maternal direction was not different from zero. The in vitro transfer rates correlated well with the transfer rates estimated for the in vivo situation from data published in the literature. CONCLUSION: There is a significant active transport of Ca++ across the human placenta in the maternal-fetal direction.

• MeSH
• aktivní transport účinky léků   fyziologie   MeSH
• EDTA farmakokinetika   MeSH
• kyanid sodný farmakologie   MeSH
• lidé MeSH
• maternofetální výměna látek účinky léků   fyziologie   MeSH
• perfuze MeSH
• placenta anatomie a histologie   metabolismus   MeSH
• techniky in vitro MeSH
• těhotenství MeSH
• vápník farmakokinetika   MeSH
• velikost orgánu MeSH
• verapamil farmakologie   MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• EDTA MeSH
• kyanid sodný MeSH
• vápník MeSH
• verapamil MeSH

1. In order to investigate mechanisms of Na+ transfer, the unidirectional maternal-fetal clearance (Kmf) of 22Na+ and of 51Cr-EDTA (a marker of paracellular diffusion) was measured across the intact or umbilically or dually perfused placenta of the anaesthetized rat. 2. The Kmf of 22Na+ in the intact preparation (18.5 +/- 2.7 microliters min-1, mean +/- S.D., n = 105 placentas) exceeded that of 51Cr-EDTA in the same experiments (1.4 +/- 0.3 microliters min-1) by more than ten times, whereas the difference in their diffusion coefficients in water was only 2-fold. In the perfused preparations the difference in the Kmf values was 6-fold. 3. Assuming that a simple model of paracellular diffusion through wide pores was one component of transfer, the Kmf of 51Cr-EDTA and the diffusion coefficients were used to calculate a component of 22Na+ clearance (Kmf,residual) and of Na+ flux (Jmf,residual) across the perfused placentas which could not be accounted for by transfer through the paracellular route. 4. Kmf,residual of 22Na+ across the dually perfused placenta was significantly lower when temperature was reduced, the temperature quotient (Q10) of the transfer being about 2. Kmf,residual was also significantly lower when 0.1 mM ouabain was perfused on the fetal side. Jmf,residual exhibited saturation kinetics characterized by an apparent Michaelis constant (Km) of 90 mM. Kmf,residual was not influenced by 0.5 mM frusemide, 0.5 mM amiloride or by 0.5 mM hydrochlorothiazide administered to the maternal side. It was significantly increased by 1 mM alanine on the maternal side suggesting that the coupled transfer of Na+ and amino acids may contribute significantly to the maternal-fetal flux of Na+. 5. These observations suggest that most (80%) of the maternal-fetal flux of Na+ across the rat placenta is effected by active transcellular transport. This transport involves passive entry of Na+ into the trophoblast from the maternal side by a largely unknown saturable mechanism and active extrusion of Na+ from trophoblast to the fetal side by Na(+)-K(+)-ATPase.

• MeSH
• aktivní transport účinky léků   MeSH
• anestezie MeSH
• difuze MeSH
• diuretika farmakologie   MeSH
• EDTA metabolismus   MeSH
• fenazon metabolismus   MeSH
• kinetika MeSH
• krysa rodu Rattus MeSH
• maternofetální výměna látek fyziologie   MeSH
• nízká teplota MeSH
• ouabain farmakologie   MeSH
• placenta metabolismus   MeSH
• potkani Wistar MeSH
• sodík metabolismus   MeSH
• techniky in vitro MeSH
• těhotenství MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• diuretika MeSH
• EDTA MeSH
• fenazon MeSH
• ouabain MeSH
• sodík MeSH