- MeSH
- chronická pankreatitida metabolismus patofyziologie MeSH
- chuťová percepce MeSH
- Crohnova nemoc metabolismus patofyziologie MeSH
- cystická fibróza metabolismus patofyziologie MeSH
- enterocyty fyziologie MeSH
- gastrointestinální absorpce fyziologie MeSH
- gastrointestinální nemoci * metabolismus patofyziologie MeSH
- kyselina linolová metabolismus MeSH
- lidé MeSH
- mastné kyseliny * fyziologie metabolismus MeSH
- potravinová intolerance MeSH
- střeva metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
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.
- 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
- MeSH
- dospělí MeSH
- intestinální absorpce fyziologie MeSH
- lidé MeSH
- makrocytární anemie etiologie farmakoterapie MeSH
- nedostatek vitaminu B12 farmakoterapie MeSH
- potravní doplňky MeSH
- rizikové faktory MeSH
- senioři MeSH
- vitamin B 12 * fyziologie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
- kongresy MeSH
- zprávy 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.
- 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
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.
- 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
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.
- 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
Mycotoxin management in agriculture is an essential challenge for maintaining the health of both animals and humans. Choosing the right adsorbent is still a question for many breeders and an important criterion for feed manufacturers. New adsorbents are still being sought. Graphene oxide is a promising material in the field of nanotechnology, which excels in its adsorption properties. Presented in vitro study investigates graphene oxide for the binding of mycotoxins from crushed wheat. The results show that graphene oxide has an adsorption capacity for aflatoxin 0.045 mg/g, zearalenone 0.53 mg/g and deoxynivalenol 1.69 mg/g at 37° C. In vitro simulation of crushed wheat digestion showed rapid adsorption during the gastric phase. Of the minerals, Mg, Cu and Zn were the most adsorbed. The applied dose of graphene oxide of 10 mg/g caused only a slight inhibition of the digestive enzymes α-amylase and trypsin compared to pepsin and gastric lipase. In vitro results indicated the suitability of graphene oxide in the adsorption of the aflatoxin, zearalenone and deoxynivalenol.
- MeSH
- adsorpce MeSH
- aflatoxin B1 izolace a purifikace toxicita MeSH
- gastrointestinální absorpce MeSH
- grafit chemie MeSH
- kontaminace potravin analýza prevence a kontrola MeSH
- krmivo pro zvířata analýza toxicita MeSH
- lidé MeSH
- mykotoxiny izolace a purifikace toxicita MeSH
- nanostruktury chemie MeSH
- pšenice chemie toxicita MeSH
- techniky in vitro MeSH
- trávení MeSH
- trichotheceny izolace a purifikace toxicita MeSH
- zearalenon izolace a purifikace toxicita MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem 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.
- 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
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.
- 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
