BACKGROUND AND PURPOSE: Lymphatic transport of drugs after oral administration is an important mechanism for absorption of highly lipophilic compounds. Direct measurement in lymph duct cannulated animals is the gold standard method, but non-invasive cycloheximide chylomicron flow blocking method has gained popularity recently. However, concerns about its reliability have been raised. The aim of this work was to investigate the validity of cycloheximide chylomicron flow blocking method for the evaluation of lymphatic transport using model compounds with high to very high lipophilicity, that is, abiraterone and cinacalcet. EXPERIMENTAL APPROACH: Series of pharmacokinetic studies were conducted with abiraterone acetate and cinacalcet hydrochloride after enteral/intravenous administration to intact, lymph duct cannulated and/or cycloheximide pre-treated rats. KEY RESULTS: Mean total absolute oral bioavailability of abiraterone and cinacalcet was 7.0% and 28.7%, respectively. There was a large and significant overestimation of the lymphatic transport extent by the cycloheximide method. Mean relative lymphatic bioavailability of abiraterone and cinacalcet in cycloheximide method was 28-fold and 3-fold higher than in cannulation method, respectively. CONCLUSION AND IMPLICATIONS: Cycloheximide chylomicron flow blocking method did not provide reliable results on lymphatic absorption and substantially overestimated lymphatic transport for both molecules, that is, abiraterone and cinacalcet. This non-invasive method should not be used for the assessment of lymphatic transport and previously obtained data should be critically revised.

• Klíčová slova
• abiraterone, bioavailability, biodistribution, cinacalcet, lymph duct cannulation, pharmacokinetics,
• MeSH
• aplikace orální MeSH
• biologická dostupnost MeSH
• biologický transport MeSH
• chylomikrony * metabolismus   MeSH
• cykloheximid farmakologie   MeSH
• intestinální absorpce * MeSH
• krysa rodu Rattus MeSH
• léčivé přípravky MeSH
• reprodukovatelnost výsledků MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chylomikrony * MeSH
• cykloheximid MeSH
• léčivé přípravky MeSH

Metformin, an oral antidiabetic drug, recently demonstrated a reducing effect on bile acids (BA) plasma concentrations in one patient with intrahepatic cholestasis of pregnancy (ICP) by unknown mechanism. Therefore, the aim of the present study was to examine the effect of metformin on BA homeostasis and related molecular pathways in the liver and intestine using a mouse model of ICP. The cholestasis was induced in female C57BL/6 mice by repeated administration of ethinylestradiol (10 mg/kg BW s.c.) and/or metformin (150 mg/kg BW orally) over 5 consecutive days with subsequent bile collection and molecular analysis of samples. We demonstrated that metformin significantly increased the rate of bile secretion in control mice. This increase was BA dependent and was produced both by increased liver BA synthesis via induced cholesterol 7α-hydroxylase (Cyp7a1) and by increased BA reabsorption in the ileum via induction of the apical sodium-dependent BA transporter (Asbt). In contrast, metformin further worsened ethinylestradiol-induced impairment of bile secretion. This reduction was also BA dependent and corresponded with significant downregulation of Bsep, and Ntcp, major excretory and uptake transporters for BA in hepatocytes, respectively. The plasma concentrations of BA were consequently significantly increased in the metformin-treated mice. Altogether, our data indicate positive stimulation of bile secretion by metformin in the intact liver, but this drug also induces serious impairment of BA biliary secretion, with a marked increase in plasma concentrations in estrogen-induced cholestasis. Our results imply that metformin should be used with caution in situations with hormone-dependent cholestasis, such as ICP.

• Klíčová slova
• Bile, Cholestasis, Ethinylestradiol, Metformin,
• MeSH
• cholestáza chemicky indukované   metabolismus   patologie   MeSH
• ethinylestradiol škodlivé účinky   MeSH
• hepatocyty účinky léků   metabolismus   MeSH
• homeostáza účinky léků   MeSH
• intestinální absorpce účinky léků   MeSH
• metformin farmakologie   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• žlučové kyseliny a soli metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ethinylestradiol MeSH
• metformin MeSH
• žlučové kyseliny a soli MeSH

Although oral drug delivery is the preferred administration route and has been used for centuries, modern drug discovery and development pipelines challenge conventional formulation approaches and highlight the insufficient mechanistic understanding of processes critical to oral drug absorption. This review presents the opinion of UNGAP scientists on four key themes across the oral absorption landscape: (1) specific patient populations, (2) regional differences in the gastrointestinal tract, (3) advanced formulations and (4) food-drug interactions. The differences of oral absorption in pediatric and geriatric populations, the specific issues in colonic absorption, the formulation approaches for poorly water-soluble (small molecules) and poorly permeable (peptides, RNA etc.) drugs, as well as the vast realm of food effects, are some of the topics discussed in detail. The identified controversies and gaps in the current understanding of gastrointestinal absorption-related processes are used to create a roadmap for the future of oral drug absorption research.

• Klíčová slova
• Advanced formulations, Amorphous solid dispersions, Food-drug interactions, In vitro tools, Lipid-based formulations, Microbiome, PBPK modeling, Regional differences, Specific patient populations,
• MeSH
• aplikace orální MeSH
• gastrointestinální trakt metabolismus   MeSH
• interakce mezi potravou a léky MeSH
• intestinální absorpce * MeSH
• léčivé přípravky chemie   metabolismus   MeSH
• lidé MeSH
• počítačová simulace MeSH
• příprava léků MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• léčivé přípravky MeSH

The determination of mycotoxins content in food is not sufficient for the prediction of their potential in vivo cytotoxicity because it does not reflect their bioavailability and mutual interactions within complex matrices, which may significantly alter the toxic effects. Moreover, many mycotoxins undergo biotransformation and metabolization during the intestinal absorption process. Biotransformation is predominantly the conversion of mycotoxins meditated by cytochrome P450 and other enzymes. This should transform the toxins to nontoxic metabolites but it may possibly result in unexpectedly high toxicity. Therefore, the verification of biotransformation and bioavailability provides valuable information to correctly interpret occurrence data and biomonitoring results. Among all of the methods available, the in vitro models using monolayer formed by epithelial cells from the human colon (Caco-2 cell) have been extensively used for evaluating the permeability, bioavailability, intestinal transport, and metabolism of toxic and biologically active compounds. Here, the strengths and limitations of both in vivo and in vitro techniques used to determine bioavailability are reviewed, along with current detailed data about biotransformation of mycotoxins. Furthermore, the molecular mechanism of mycotoxin effects is also discussed regarding the disorder of intestinal barrier integrity induced by mycotoxins.

• Klíčová slova
• bioavailability, biotransformation, cytochrome, intestinal transport, metabolism, mycotoxins, permeability,
• MeSH
• biologická dostupnost MeSH
• Caco-2 buňky MeSH
• epitelové buňky enzymologie   MeSH
• hodnocení rizik MeSH
• intestinální absorpce * MeSH
• lidé MeSH
• metabolická aktivace MeSH
• metabolická inaktivace MeSH
• mykotoxiny metabolismus   toxicita   MeSH
• permeabilita MeSH
• střevní sliznice enzymologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• mykotoxiny MeSH

PURPOSE: To provide a comprehensive and up-to-date overview focusing on the extent of lymphatic transport of drugs following intestinal absorption and to summarize available data on the impact of molecular weight, lipophilicity, formulation and prandial state. METHODS: Literature was searched for in vivo studies quantifying extent of lymphatic transport of drugs after enteral dosing. Pharmacokinetic data were extracted and summarized. Influence of molecular weight, log P, formulation and prandial state was analyzed using relative bioavailability via lymph (FRL) as the parameter for comparison. The methods and animal models used in the studies were also summarized. RESULTS: Pharmacokinetic data on lymphatic transport were available for 103 drugs. Significantly higher FRL [median (IQR)] was observed in advanced lipid based formulations [54.4% (52.0)] and oil solutions [38.9% (60.8)] compared to simple formulations [2.0% (27.1)], p < 0.0001 and p = 0.004, respectively. Advanced lipid based formulations also provided substantial FRL in drugs with log P < 5, which was not observed in simple formulations and oil solutions. No relation was found between FRL and molecular weight. There were 10 distinct methods used for in vivo testing of lymphatic transport after intestinal absorption so far. CONCLUSION: Advanced lipid based formulations provide superior ability to increase lymphatic absorption in drugs of various molecular weights and in drugs with moderate to low lipophilicity.

• Klíčová slova
• animal models, bioavailability, lipid based formulations, lymph duct cannulation, lymphatic absorption,
• MeSH
• aplikace orální MeSH
• biologická dostupnost MeSH
• biologický transport fyziologie   MeSH
• databáze bibliografické MeSH
• farmakokinetika MeSH
• intestinální absorpce MeSH
• léčivé přípravky MeSH
• lékové transportní systémy MeSH
• lidé MeSH
• lymfatický systém metabolismus   MeSH
• modely u zvířat MeSH
• příprava léků metody   statistika a číselné údaje   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• léčivé přípravky MeSH

Matrix-Liposomes (MLs) are a very promising solid oral drug delivery system; however, data on their interaction with biological membranes are not available. Here, we describe the quality of MLs manufactured by dual centrifugation. MLs were prepared with a Z-average range of 139 to 160 nm and a PDI of 0.18 to 0.25. To investigate the effect of MLs on intestinal tissue (with and without mucolytic treatment), we then established an ex vivo rat intestine model. The integrity of the epithelial membranes of rat intestine was not affected by the incubation with MLs without or with pre-mucolytic treatment. Tissue samples were also analysed for changes in P-glycoprotein (P-gp) expression and function. The net secretion of the P-gp substrate Rh123 across the rat duodenum was increased in the presence of MLs. To summarize, MLs do not affect intestinal epithelial integrity, although they impact Rh123 secretion. In future, these novel MLs have to be further evaluated for proficient intestinal drug delivery.

• Klíčová slova
• Drug transporters, Dual centrifugation, Intestine, Liposomes, Oral peptide drug delivery, Ussing Chamber,
• MeSH
• biologické přípravky chemie   MeSH
• biologický transport fyziologie   MeSH
• duodenum metabolismus   MeSH
• intestinální absorpce fyziologie   MeSH
• krysa rodu Rattus MeSH
• liposomy chemie   MeSH
• P-glykoprotein metabolismus   MeSH
• střevní sliznice metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• biologické přípravky MeSH
• liposomy MeSH
• P-glykoprotein MeSH

The aim of our study was to assess the presence and degree of intestinal leakage in subjects suffering from short bowel syndrome (SBS) and its modification by parenteral nutrition. To this end we assessed circulating levels of selected makers of intestinal permeability including zonulin, fatty acid binding protein 2 (FABP-2), citrulline and glucagon-like peptide 2 (GLP-2). We also measured lipopolysaccharide binding protein (LBP) as a marker of circulating levels of lipopolysaccharide acting through the CD14 molecule. Eleven SBS and 10 age- and BMI-matched control subjects were included into the study. The effect of parenteral nutrition was assessed after 14 days, 6 and 12 months from its initiation, respectively. At baseline, SBS patients had increased gut permeability as measured by zonulin (47.24+/-2.14 vs. 39.48+/-1.20 ng/ml, p=0.006) and LBP (30.32+/-13.25 vs. 9.77+/-0.71 microg/ml, p<0.001) compared to healthy controls. Furthermore, SBS subjects had reduced FABP-2, unchanged citrulline and increased sCD14 and GLP-2 relative to control group. Throughout the whole study period the administered parenteral nutrition had no significant effect on any of the studied parameters. Taken together, our data show that patients with short bowel syndrome have increased intestinal permeability that is not affected by parenteral nutrition.

• MeSH
• biologické markery krev   MeSH
• citrulin krev   MeSH
• glukagonu podobný peptid 2 krev   MeSH
• haptoglobiny MeSH
• intestinální absorpce * MeSH
• lidé středního věku MeSH
• lidé MeSH
• membránové glykoproteiny krev   MeSH
• parenterální výživa * MeSH
• permeabilita MeSH
• proteinové prekurzory krev   MeSH
• proteiny akutní fáze MeSH
• proteiny vázající mastné kyseliny krev   MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• syndrom krátkého střeva krev   diagnóza   patofyziologie   terapie   MeSH
• tenké střevo metabolismus   patofyziologie   MeSH
• transportní proteiny krev   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• biologické markery MeSH
• citrulin MeSH
• FABP2 protein, human MeSH Prohlížeč
• glukagonu podobný peptid 2 MeSH
• haptoglobiny MeSH
• lipopolysaccharide-binding protein MeSH Prohlížeč
• membránové glykoproteiny MeSH
• proteinové prekurzory MeSH
• proteiny akutní fáze MeSH
• proteiny vázající mastné kyseliny MeSH
• transportní proteiny MeSH
• zonulin MeSH Prohlížeč

The study was focused on assessment of potential health risks of paper-based food contact materials (FCMs) in a step-wise approach using three toxicological bioassays in vitro and chemical analyses of migrating contaminants. 3T3 NRU cytotoxicity test showed high sensitivity to detect basal toxicity of FCMs extracts and served as a first-line test for selection of samples for further testing. The reconstructed human intestine model EpiIntestinal showed more realistic tissue response than cell culture monolayer and higher resistance despite prolonged exposure to the selected 6 samples, i.e. negligible decrease of viability and intestinal penetration, nevertheless an increase of IL-8 after exposure to black printed sample extract. Yeast based assays identified weak agonistic/antagonostic activity to human androgen receptor of the black printed sample. In accordance with the biological effects, the targeted LC and GC analytical methods confirmed the presence of high amounts of phthalates, photoinitiators and PAHs that could justify the hazard of the black printed sample. Heavily printed uncoated FCMs are recognized not to be suitable for direct contact with food. The selected bioassays and chemical analyses might be useful tools to detect targeted biological effects of xenobiotics suspected to contribute to human exposure from food.

• Klíčová slova
• Chemical analysis, Cytotoxicity, Endocrine disruption, Food contact material, Paper-based, Reconstructed human intestine model,
• MeSH
• androgenní receptory genetika   metabolismus   MeSH
• biotest MeSH
• buňky BALB 3T3 MeSH
• cytokiny metabolismus   MeSH
• hodnocení rizik MeSH
• intestinální absorpce MeSH
• kontaminace potravin MeSH
• kyseliny ftalové analýza   toxicita   MeSH
• lidé MeSH
• myši MeSH
• obaly potravin * MeSH
• papír * MeSH
• polycyklické aromatické uhlovodíky analýza   toxicita   MeSH
• receptory pro estrogeny genetika   metabolismus   MeSH
• Saccharomyces cerevisiae genetika   MeSH
• střevní sliznice účinky léků   metabolismus   MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• androgenní receptory MeSH
• cytokiny MeSH
• kyseliny ftalové MeSH
• polycyklické aromatické uhlovodíky MeSH
• receptory pro estrogeny MeSH

The simultaneous intake of food and drugs can have a strong impact on drug release, absorption, distribution, metabolism and/or elimination and consequently, on the efficacy and safety of pharmacotherapy. As such, food-drug interactions are one of the main challenges in oral drug administration. Whereas pharmacokinetic (PK) food-drug interactions can have a variety of causes, pharmacodynamic (PD) food-drug interactions occur due to specific pharmacological interactions between a drug and particular drinks or food. In recent years, extensive efforts were made to elucidate the mechanisms that drive pharmacokinetic food-drug interactions. Their occurrence depends mainly on the properties of the drug substance, the formulation and a multitude of physiological factors. Every intake of food or drink changes the physiological conditions in the human gastrointestinal tract. Therefore, a precise understanding of how different foods and drinks affect the processes of drug absorption, distribution, metabolism and/or elimination as well as formulation performance is important in order to be able to predict and avoid such interactions. Furthermore, it must be considered that beverages such as milk, grapefruit juice and alcohol can also lead to specific food-drug interactions. In this regard, the growing use of food supplements and functional food requires urgent attention in oral pharmacotherapy. Recently, a new consortium in Understanding Gastrointestinal Absorption-related Processes (UNGAP) was established through COST, a funding organisation of the European Union supporting translational research across Europe. In this review of the UNGAP Working group "Food-Drug Interface", the different mechanisms that can lead to pharmacokinetic food-drug interactions are discussed and summarised from different expert perspectives.

• Klíčová slova
• Absorption, Drug release, Food effect, Food-drug interaction, Metabolism, Oral bioavailability, Oral drug delivery,
• MeSH
• aplikace orální MeSH
• biologická dostupnost MeSH
• farmakokinetika MeSH
• gastrointestinální absorpce fyziologie   MeSH
• gastrointestinální trakt fyziologie   MeSH
• interakce mezi potravou a léky fyziologie   MeSH
• intestinální absorpce MeSH
• lidé MeSH
• uvolňování léčiv fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Geografické názvy
• Evropa MeSH

BACKGROUND: In recent years the number of natural products used as pharmaceuticals, components of dietary supplements and cosmetics has increased tremendously requiring more extensive evaluation of their pharmacokinetic properties. PURPOSE: This study aims at combining in vitro and in silico methods to evaluate the gastrointestinal absorption (GIA) of natural flavonolignans from milk thistle (Silybum marianum (L.) Gaertn.) and their derivatives. METHODS: A parallel artificial membrane permeability assay (PAMPA) was used to evaluate the transcellular permeability of the plant main components. A dataset of 269 compounds with measured PAMPA values and specialized software tools for calculating molecular descriptors were utilized to develop a quantitative structure-activity relationship (QSAR) model to predict PAMPA permeability. RESULTS: The PAMPA permeabilities of 7 compounds constituting the main components of the milk thistle were measured and their GIA was evaluated. A freely-available and easy to use QSAR model predicting PAMPA permeability from calculated physico-chemical molecular descriptors was derived and validated on an external dataset of 783 compounds with known GIA. The predicted permeability values correlated well with obtained in vitro results. The QSAR model was further applied to predict the GIA of 31 experimentally untested flavonolignans. CONCLUSIONS: According to both in vitro and in silico results most flavonolignans are highly permeable in the gastrointestinal tract, which is a prerequisite for sufficient bioavailability and use as lead structures in drug development. The combined in vitro/in silico approach can be used for the preliminary evaluation of GIA and to guide further laboratory experiments on pharmacokinetic characterization of bioactive compounds, including natural products.

• Klíčová slova
• Flavonolignans, Gastrointestinal absorption, PAMPA, QSAR, Silybum marianum,
• MeSH
• flavonoidy chemie   farmakokinetika   MeSH
• flavonolignany farmakokinetika   MeSH
• intestinální absorpce účinky léků   MeSH
• kvantitativní vztahy mezi strukturou a aktivitou * MeSH
• lidé MeSH
• membrány umělé MeSH
• ostropestřec mariánský chemie   MeSH
• permeabilita buněčné membrány účinky léků   MeSH
• počítačová simulace MeSH
• potravní doplňky MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• flavonoidy MeSH
• flavonolignany MeSH
• membrány umělé MeSH