Introduction: Solute Carrier (SLC) and ATP-binding cassette (ABC) transporters expressed in the intestine, liver, and kidney determine the absorption, distribution, and excretion of drugs. In addition, most molecular and cellular processes show circadian rhythmicity controlled by circadian clocks that leads to diurnal variations in the pharmacokinetics and pharmacodynamics of many drugs and affects their therapeutic efficacy and toxicity.Area covered: This review provides an overview of the current knowledge on the circadian rhythmicity of drug transporters and the molecular mechanisms of their circadian control. Evidence for coupling drug transporters to circadian oscillators and the plausible candidates conveying circadian clock signals to target drug transporters, particularly transcription factors operating as the output of clock genes, is discussed.Expert opinion: The circadian machinery has been demonstrated to interact with the uptake and efflux of various drug transporters. The evidence supports the concept that diurnal changes that affect drug transporters may influence the pharmacokinetics of the drugs. However, more systematic studies are required to better define the timing of pharmacologically important drug transporter regulation and determine tissue- and sex-dependent differences. Finally, the transfer of knowledge based on the results and conclusions obtained primarily from animal models will require careful validation before it is applied to humans.

• MeSH
• ABC transportéry genetika   fyziologie   MeSH
• časové faktory MeSH
• cirkadiánní rytmus fyziologie   MeSH
• farmakokinetika MeSH
• léčivé přípravky metabolismus   MeSH
• lidé MeSH
• sexuální faktory MeSH
• SLC transportéry genetika   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Potrava, některé její složky, nápoje a potravinové doplňky často ovlivňují metabolismus a transport léčiv v organismu nebo přímo farmakodynamické účinky léčiv. V důsledku těchto interakcí dochází ke změnám v biologické dostupnosti léčiv, ke snížení účinku nebo selhání terapie nebo ke zvýšení rizika výskytu nežádoucích účinků, výjimečně dokonce může dojít k projevům toxicity. Cílem přehledu je podat základní informaci o rozsahu aktuálních znalostí o interakcích potravy a nápojů s léčivy. Zejména pak ukázat na léčiva, která je z různých důvodů nezbytné užívat bud' nalačno, nebo po jídle a současně upozornit na skutečnost, že se léčiva mají zapíjet vodou.

Food, some of its ingredients, drinks and dietary supplements often affect the metabolism and transport of drugs in the body or directly the pharmacodynamic effects of drugs. As a result of these interactions, there is a change in the bioavailability of the drugs, in reducing the effect or failure of the therapy, or in increasing the risk of adverse reactions, and in exceptional cases there may be signs of toxicity. The aim of the review is to provide basic information about the extent of current knowledge about food and drink interactions with drugs. In particular, point to medicines that, for various reasons, need to be taken either on an empty stomach or after a meal, and at the same time to draw attention to the fact that medicines should be swallowed with water.

• MeSH
• ABC transportéry agonisté   antagonisté a inhibitory   fyziologie   MeSH
• abirateron terapeutické užití   MeSH
• absorpce v žaludku fyziologie   MeSH
• alkoholické nápoje škodlivé účinky   MeSH
• aplikace orální MeSH
• biologická dostupnost MeSH
• čaj enzymologie   fyziologie   MeSH
• enterocyty enzymologie   fyziologie   metabolismus   MeSH
• farmakoterapie metody   MeSH
• fyziologie výživy fyziologie   MeSH
• glukagonu podobný peptid 1 fyziologie   MeSH
• interakce bylin a léků fyziologie   MeSH
• interakce mezi potravou a léky * fyziologie   MeSH
• lidé MeSH
• mléko MeSH
• nežádoucí účinky léčiv MeSH
• ovocné a zeleninové šťávy škodlivé účinky   MeSH
• SLC transportéry agonisté   antagonisté a inhibitory   fyziologie   MeSH
• sycené nápoje škodlivé účinky   MeSH
• systém (enzymů) cytochromů P-450 fyziologie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH
• přehledy MeSH

Ribavirin is a broad-spectrum nucleoside-derived antiviral drug used in combination pharmacotherapy treatment of hepatitis C virus infection. Current evidence indicates that ribavirin-associated teratogenicity is not significant in humans, but more information about the developmental toxicity and mechanisms involved in ribavirin placental kinetics is required to assure its safe use in pregnancy. Thus, we have investigated potential roles of equilibrative nucleoside transporters (ENTs, SLC29A), Na+-dependent influx-mediating concentrative nucleoside transporters (CNTs, SLC28A), and ATP-binding cassette (ABC) efflux pumps, in ribavirin placental pharmacokinetics. Our data indicate that ENT1 participates in uptake of ribavirin by BeWo cells, fresh human placental villous fragments and microvillous plasma membrane (MVM) vesicles while activity of CNTs (probably CNT2) was only observed in BeWo cells. In situ dual perfusion experiments with rat term placenta in an open circuit setup showed that ENT inhibition significantly decreases total ribavirin maternal-to-foetal and foetal-to-maternal clearances. In contrast, no contribution of ABC transporters, p-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2), or multidrug resistance-associated protein (ABCC2) was detected in assays with MDCKII cells overexpressing them, or in closed circuit dual perfusion experiments with rat term placenta. In summary, our data show that ribavirin placental pharmacokinetics are largely controlled by ENT1 activity and independent of ABCB1, ABCG2, and ABCC2 efflux pumps.

• MeSH
• ABC transportéry fyziologie   MeSH
• antimetabolity metabolismus   farmakologie   MeSH
• buňky MDCK MeSH
• druhová specificita MeSH
• ekvilibrační přenašeč nukleosidů 1 metabolismus   MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nukleosidy fyziologie   MeSH
• placenta účinky léků   metabolismus   MeSH
• potkani Wistar MeSH
• psi MeSH
• ribavirin metabolismus   farmakologie   MeSH
• těhotenství MeSH
• transport proteinů účinky léků   fyziologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• psi MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• ABC transportéry * biosyntéza   fyziologie   genetika   MeSH
• biologické modely MeSH
• biologický transport fyziologie   genetika   MeSH
• fungální léková rezistence fyziologie   genetika   MeSH
• houby * fyziologie   genetika   MeSH
• nemoci rostlin mikrobiologie   MeSH

V předcházejících číslech tohoto časopisu bylo probráno působení farmak na úrovni receptorů nebo enzymů. Tento článek je zaměřen na působení farmak na dalších dvou důležitých místech, a to na iontových kanálech a transportních bílkovinách (transportérech, přenašečích). V této oblasti je mnoho nových poznatků rozptýlených v mnoha časopisech, které dosud nebyly souborně, přehledně a srozumitelně publikovány z hlediska klinika. Článek o to usiluje. Probírá úlohu iontových kanálů a transportérů typu ABC nebo SLC v terapeutických účincích mnoha klinicky významných farmak (např. blokátorů vápníkových kanálů, lokálních anestetik, antiepileptik, digoxinu, inhibitorů protonové pumpy, antidepresiv, některých antidiabetik aj.).

In recent issues of this journal, two review articles were published focused on drug effects on receptors and enzymes. This article is focused on the effects of drugs on two other important sites, on ion channels and ion and molecule transporters. A plethora of new findings on this topic have been published and distributed in many journals. An article reviewing these findings comprehensively, but concisely and clearly in a way convenient for a busy clinician is lacking. The present paper attempts to provide such a review. It reviews the role of ion channels and ABC and SLC transporters in the therapeutic effects of many important drugs (e.g. calcium channel blockers, local anaesthetics, anticonvulsants, digoxin, proton pump inhibitors, antidepressants, some antidiabetics).

• MeSH
• ABC transportéry farmakologie   fyziologie   účinky léků   MeSH
• aktivní transport fyziologie   účinky léků   MeSH
• iontové kanály * účinky léků   MeSH
• iontové pumpy farmakologie   fyziologie   účinky léků   MeSH
• iontový transport fyziologie   účinky léků   MeSH
• membránové transportní proteiny * farmakologie   fyziologie   účinky léků   MeSH
• sodíkové kanálky řízené napětím farmakologie   fyziologie   účinky léků   MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

α-Tocopheryl succinate (α-TOS) is a promising anti-cancer agent due to its selectivity for cancer cells. It is important to understand whether long-term exposure of tumour cells to the agent will render them resistant to the treatment. Exposure of the non-small cell lung carcinoma H1299 cells to escalating doses of α-TOS made them resistant to the agent due to the upregulation of the ABCA1 protein, which caused its efflux. Full susceptibility of the cells to α-TOS was restored by knocking down the ABCA1 protein. Similar resistance including ABCA1 gene upregulation was observed in the A549 lung cancer cells exposed to α-TOS. The resistance of the cells to α-TOS was overcome by its mitochondrially targeted analogue, MitoVES, that is taken up on the basis of the membrane potential, bypassing the enhanced expression of the ABCA1 protein. The in vitro results were replicated in mouse models of tumours derived from parental and resistant H1299 cells. We conclude that long-term exposure of cancer cells to α-TOS causes their resistance to the drug, which can be overcome by its mitochondrially targeted counterpart. This finding should be taken into consideration when planning clinical trials with vitamin E analogues.

• MeSH
• ABC transportéry genetika   fyziologie   MeSH
• ABCA1 protein MeSH
• alfa-tokoferol terapeutické užití   MeSH
• chemorezistence * MeSH
• genový knockdown MeSH
• mitochondrie účinky léků   MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory plic farmakoterapie   MeSH
• nemalobuněčný karcinom plic farmakoterapie   MeSH
• protinádorové látky farmakologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Transportné proteíny z rodiny ABC (ATP-binding cassette) zabezpečujú transport rôznych substrátov cez biologické membrány. Zohrávajú esenciálnu úlohu v ochrane buniek pred toxickými zlúčeninami/metabolitmi. S nadexpresiou ABC transportných proteínov súvisí vznik mnohonásobnej rezistencie (MDR, multidrug resistance) buniek voči antimikróbnym zlúčeninám a protinádorovým chemoterapeutikám. Mutácie proteínov ABC-typu u ľudí sú príčinou viacerých genetických ochorení (cystická fibróza, adrenoleukodystrofia, defekty v transporte cholesterolu, žlče a pod.). Bunky mikroorganizmov obsahujú viaceré homológy klinicky významných ABC proteínov. Ich intenzívne molekulárne štúdium môže prispieť k návrhu nových postupov ako zvládnuť MDR resp. ochorenia, ktoré sú dôsledkom dysfunkcie ABC proteínov. Práca podáva prehľad súčasného stavu poznatkov o ABC transportných proteínoch v bunkách prokaryotických a eukaryotických mikroorganizmov.

The ABC (ATP binding cassette) transporter family includes membrane proteins that can transport a wide variety of substrates across biological membranes. These proteins play an essential role in the protection of cells from toxic compounds/metabolites. Their overexpression which leads to the development of multidrug resistance (MDR) in pathogens and enables cancer cells to survive chemotherapy is of major concern for human health. Mutations in ABC transporters are implicated in a number of Mendelian disorders such as cystic fibrosis, adrenoleukodystrophy and cholesterol and bile transport defects. In microbial cells, several homologues of human ABC transporters were identified. Their further molecular biological study can contribute to better understanding and treatment of MDR or diseases caused by dysfunction of ABC transporter proteins. A review is presented of the state of the art in ABC transporter proteins in both prokaryotic and eucaryotic cells. The role of microbial ABC transporters in the development of drug resistance is analyzed.

• MeSH
• ABC transportéry fyziologie   MeSH
• chemorezistence genetika   MeSH
• mnohočetná bakteriální léková rezistence genetika   MeSH
• mnohočetná fungální léková rezistence genetika   MeSH
• mnohočetná léková rezistence genetika   MeSH
• mnohočetná virová léková rezistence genetika   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

Like other tested wild-type strains (DTXII and IL-125-2B), exponential glucose- and/or fructose-grown cells of Saccharomyces cerevisiae BY4742 exhibit the previously described high activity of Pdr5p and Snq2p pumps (measured as export of the potentiometric fluorescent probe diS-C3(3)). Upon saccharide depletion from the medium the pump activity in these cells, which differ from other strains in having a lower membrane potential, sharply drops to a very low level similar to that found in cells grown on ethanol or glycerol. This negligible pump activity in respiring cells thus appears to have a universal character. Addition of glucose or fructose to respiring BY4742 cells grown to low culture densities restores multidrug resistance pump activity due partly to pump synthesis in pre-existing cells and partly to the high pump activity of newly grown cells; no such pump activity boost occurs when the sugar is added to high-density cultures of ethanol-grown or post-diauxic glucose-grown cells, even if these cultures are diluted to low density by their original growth-depleted medium. A strong sugar-induced increase in pump activity is found solely if respiring cells from high-density cultures are resuspended in fresh YPD or YPE medium before sugar addition. Its absence in respiring cells suspended in growth-depleted medium reflects an as yet unidentified effect of the composition of the growth-exhausted medium (depletion of some components and/or accumulation of extracellular metabolites during yeast growth) on sugar-induced pump activity rise.

• MeSH
• ABC transportéry fyziologie   MeSH
• financování organizované MeSH
• fruktosa farmakologie   MeSH
• glukosa farmakologie   MeSH
• karbocyaniny farmakologie   MeSH
• kultivační média MeSH
• membránové potenciály účinky léků   MeSH
• mnohočetná fungální léková rezistence fyziologie   MeSH
• Saccharomyces cerevisiae - proteiny fyziologie   MeSH
• Saccharomycetales fyziologie   růst a vývoj   účinky léků   MeSH

• MeSH
• ABC transportéry fyziologie   chemie   metabolismus   MeSH
• finanční podpora výzkumu jako téma MeSH
• lidé MeSH
• mutace MeSH
• nádorové proteiny fyziologie   chemie   metabolismus   MeSH
• Check Tag
• lidé MeSH