scholarly journals Drug Transport across Porcine Intestine Using an Ussing Chamber System: Regional Differences and the Effect of P-Glycoprotein and CYP3A4 Activity on Drug Absorption

Pharmaceutics ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 139 ◽  
Author(s):  
Yvonne Arnold ◽  
Julien Thorens ◽  
Stéphane Bernard ◽  
Yogeshvar Kalia
Keyword(s):  
Drug Absorption ◽  
Regional Differences ◽  
Drug Transport ◽  
Ussing Chamber ◽  
Drug Uptake ◽  
Chamber System ◽  
Apparent Permeability ◽  
Drug Permeability ◽  
Permeability Coefficients

Drug absorption across viable porcine intestines was investigated using an Ussing chamber system. The apparent permeability coefficients, Papp,pig, were compared to the permeability coefficients determined in humans in vivo, Peff,human. Eleven drugs from the different Biopharmaceutical Classification System (BCS) categories absorbed by passive diffusion with published Peff,human values were used to test the system. The initial experiments measured Papp,pig for each drug after application in a Krebs–Bicarbonate Ringer (KBR) buffer and in biorelevant media FaSSIF V2 and FeSSIF V2, mimicking fasted and fed states. Strong sigmoidal correlations were observed between Peff,human and Papp,pig. Differences in the segmental Papp,pig of antipyrine, cimetidine and metoprolol confirmed the discrimination between drug uptake in the duodenum, jejunum and ileum (and colon); the results were in good agreement with human data in vivo. The presence of the P-gp inhibitor verapamil significantly increased Papp,pig across the ileum of the P-gp substrates cimetidine and ranitidine (p < 0.05). Clotrimazole, a potent CYP3A4 inhibitor, significantly increased Papp,pig of the CYP3A4 substrates midazolam, verapamil and tamoxifen and significantly decreased the formation of their main metabolites. In conclusion, the results showed that this is a robust technique to predict passive drug permeability under fasted and fed states, to identify regional differences in drug permeability and to demonstrate the activity of P-gp and CYP3A4.

scholarly journals Drug Disposition in the Lower Gastrointestinal Tract: Targeting and Monitoring

Pharmaceutics ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 161
Author(s):  
Glenn Lemmens ◽  
Arno Van Camp ◽  
Stephanie Kourula ◽  
Tim Vanuytsel ◽  
Patrick Augustijns
Keyword(s):  
Drug Absorption ◽  
Drug Disposition ◽  
Drug Stability ◽  
Ussing Chamber ◽  
Dissolution Kinetics ◽  
Comprehensive Overview ◽  
Drug Molecules ◽  
Epithelial Physiology

The increasing prevalence of colonic diseases calls for a better understanding of the various colonic drug absorption barriers of colon-targeted formulations, and for reliable in vitro tools that accurately predict local drug disposition. In vivo relevant incubation conditions have been shown to better capture the composition of the limited colonic fluid and have resulted in relevant degradation and dissolution kinetics of drugs and formulations. Furthermore, drug hurdles such as efflux transporters and metabolising enzymes, and the presence of mucus and microbiome are slowly integrated into drug stability- and permeation assays. Traditionally, the well characterized Caco-2 cell line and the Ussing chamber technique are used to assess the absorption characteristics of small drug molecules. Recently, various stem cell-derived intestinal systems have emerged, closely mimicking epithelial physiology. Models that can assess microbiome-mediated drug metabolism or enable coculturing of gut microbiome with epithelial cells are also increasingly explored. Here we provide a comprehensive overview of the colonic physiology in relation to drug absorption, and review colon-targeting formulation strategies and in vitro tools to characterize colonic drug disposition.

scholarly journals Characterization of the Human Intestinal Drug Transport with Ussing Chamber System Incorporating Freshly Isolated Human Jejunum

2020 ◽  
Vol 49 (1) ◽  
pp. 84-93
Author(s):  
Kazuyoshi Michiba ◽  
Kazuya Maeda ◽  
Ko Kurimori ◽  
Tsuyoshi Enomoto ◽  
Osamu Shimomura ◽  
...  
Keyword(s):  
Drug Transport ◽  
Ussing Chamber ◽  
Chamber System ◽  
Intestinal Drug Transport

scholarly journals Caco-2 Cells, Biopharmaceutics Classification System (BCS) and Biowaiter

2011 ◽  
Vol 54 (1) ◽  
pp. 3-8 ◽  
Author(s):  
Libuše Smetanová ◽  
Věra Štětinová ◽  
Zbyněk Svoboda ◽  
Jaroslav Květina
Keyword(s):  
Drug Absorption ◽  
Classification System ◽  
Drug Transport ◽  
Biopharmaceutics Classification System ◽  
Phenol Red ◽  
Basolateral Side ◽  
Free Transport ◽  
Biopharmaceutics Classification

Almost all orally administered drugs are absorbed across the intestinal mucosa. The Caco-2 monolayers are used as an in vitro model to predict drug absorption in humans and to explore mechanism of drug absorption. The Caco-2 cells are derived from a human colon adenocarcinoma and spontaneously differentiate to form confluent monolayer of polarized cells structurally and functionally resembling the small intestinal epithelium. For studying drug permeability, Caco-2 cells are seeded onto the Transwell inserts with semipermeable membrane and grown to late confluence (21 days). After determination of cell viability, the integrity of monolayer is checked by phenol red permeability and by 14C-mannitol permeability. The transport from apical to basolateral (AP-BL) and basolateral to apical (BL-AP) is studied by adding the diluted drug on the apical or basolateral side and withdrawing the samples from the opposite compartment, respectively, for HPLC analysis or liquid scintillation spectrometry. Ca2+- free transport medium is used to determine paracellular component of the drug transport. On the basis of permeability and solubility, drugs can be categorized into four classes of Biopharmaceutics Classification System (BCS). For certain drugs, the BCS-based biowaiver approach can be used which enables to reduce in vivo bioequivalence studies.

scholarly journals Macroscopic Modeling of In Vivo Drug Transport in Electroporated Tissue

2016 ◽  
Vol 138 (3) ◽  
Author(s):  
Bradley Boyd ◽  
Sid Becker
Keyword(s):  
Electric Field ◽  
Mass Transport ◽  
Drug Transport ◽  
Irreversible Electroporation ◽  
Drug Uptake ◽  
Macroscopic Model ◽  
Uniform Electric Field ◽  
Macroscopic Modeling ◽  
Reversible Electroporation

This study develops a macroscopic model of mass transport in electroporated biological tissue in order to predict the cellular drug uptake. The change in the macroscopic mass transport coefficient is related to the increase in electrical conductivity resulting from the applied electric field. Additionally, the model considers the influences of both irreversible electroporation (IRE) and the transient resealing of the cell membrane associated with reversible electroporation. Two case studies are conducted to illustrate the applicability of this model by comparing transport associated with two electrode arrangements: side-by-side arrangement and the clamp arrangement. The results show increased drug transmission to viable cells is possible using the clamp arrangement due to the more uniform electric field.

scholarly journals The Advantages of the Ussing Chamber in Drug Absorption Studies

2005 ◽  
Vol 10 (5) ◽  
pp. 517-523 ◽  
Author(s):  
Yasumasa Gotoh ◽  
Noboru Kamada ◽  
Denichi Momose
Keyword(s):  
Small Intestine ◽  
Membrane Permeability ◽  
Drug Absorption ◽  
Ussing Chamber ◽  
In Vivo Studies ◽  
Glycoprotein P ◽  
Absorption Studies ◽  
High Concentrations ◽  
Absorption Percentage

By adding high concentrations of test drugs to an Ussing chamber with rat jejunum, we established a systemthat yields very high correlations between the rat absorption percentage and the membrane permeability, and that can accurately predict the absorption percentage for rats. An advantage of this technique is that, unlike the results obtained using Caco-2, the slope of the absorption/membrane-permeability curve is gentle, which facilitates a more exact prediction of the absorption percentage. In addition, the results obtained with this technique demonstrated that it could be used to evaluate the absorption percentage of drugs with an affinity for P-glycoprotein (P-gp), which cannot be assessed using Caco-2. Thismethod also allows for cassette screening, whichwould facilitate evaluation of the contribution of P-gp to absorption in the small intestine. Cassette screening showed that absorption of fexofenadinewas unaffected by combinationwith the P-gp substrate ketoconazole. Consistent with this finding, in vivo studies showed that ketoconazole did not affect the Fa Fg for fexofenadine, a pharmacokinetic parameter that reflects absorption and bioavailability in the small intestine. This confirms the usefulness of the Ussing chamber for cassette screening and also suggests that intestinal P-gp has a minimal contribution to drug absorption.

Transalveolar transport of large polar solutes (sucrose, inulin, and dextran)

1975 ◽  
Vol 229 (4) ◽  
pp. 989-996 ◽  
Author(s):  
J Theodore ◽  
ED Robin ◽  
R Gaudio ◽  
J Acevedo
Keyword(s):  
Diffusion Coefficients ◽  
Frog Skin ◽  
Alveolar Epithelium ◽  
Total Resistance ◽  
Free Diffusion ◽  
Apparent Permeability ◽  
Permeability Coefficients ◽  
Polar Solutes ◽  
Barrier Resistance

The in vivo transalveolar transport of three large polar solutes, sucrose, inulin, and dextran (mol wt 60,000-90,00), was compared with the transport of urea in saline-filled dog lung. Apparent permeability coefficents (p', in cm X sec-1 X 10(6)) were as follows; urea: 2.4 +/- 0.28 (SD) greater than sucrose: 0.64 +/- 0.31 (P less than 0.001) greater than inulin: 0.12 +/- .05 (P less than 0.001)--not different from dextran (mol wt 60,000-90,000): 0.08 +/- .02 (P greater then .01). Calculation of the resistance of the alveolar epithelium compared to total barrier resistance for the various solutes indicates that approximately 90% of the total resistance resides in the alveolar epithelium. Comparison of the ratio of permeability coefficients to the ratio of free-diffusion coefficients in water shows similar values for the three large polar solutes, suggesting that permeation through the alveolar epithelium occurs by means of water-filled channels. The values for permeability coefficients of alveolar epithelium fit into the spectrum of values reported for other epithelial structures (including gall bladder, frog skin, and toad bladder); it seems to have a system of channels with a small number of wide "pores" (greater than 80 A) that permit permeation of large polar solutes and is not a relatively homogeneous structure.

scholarly journals Microflow-Based Device for In Vitro and Ex Vivo Drug Permeability Studies

2020 ◽  
Vol 25 (5) ◽  
pp. 455-462
Author(s):  
Samu Hemmilä ◽  
Marika Ruponen ◽  
Elisa Toropainen ◽  
Unni Tengvall-Unadike ◽  
Arto Urtti ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Ussing Chamber ◽  
Cell Models ◽  
Excellent Correlation ◽  
Apparent Permeability ◽  
Drug Permeability ◽  
Test Conditions ◽  
Permeability Studies ◽  
Ex Vivo Tissues

This paper presents a novel microflow-based concept for studying the permeability of in vitro cell models or ex vivo tissues. Using the proposed concept, we demonstrate how to maintain physiologically relevant test conditions and produce highly reproducible permeability values for a range (31) of drug compounds. The apparent permeability coefficients ( Papp) showed excellent correlation (0.89) with the values from experiments performed with a conventional Ussing chamber. Additionally, the microflow-based concept produces notably more concentrated samples than the conventional Ussing chamber-based approach, despite the fact that more than 10 times smaller quantities of test compounds and biological membranes are needed in the microflow-based concept.

scholarly journals Soybean Milk Inhibits Absorption and Intestinal Transmembrane Transport of Gegen in Rats

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Xiao Ling ◽  
Yuqiang Xiang ◽  
Qingfa Tang ◽  
Zhen Jin ◽  
Feilong Chen ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Ussing Chamber ◽  
Transmembrane Transport ◽  
Maximum Plasma ◽  
Apparent Permeability ◽  
Time Curve ◽  
Soybean Milk ◽  
Rich Food

Puerariae Lobatae Radix, known as Gegen in Chinese, is widely used to treat cardiovascular diseases, diabetes, and many other chronic illnesses. Flavonoids are the main active components in Gegen and are found in high concentrations in soybeans. Few studies, however, have focused on the effects of flavonoid-rich food on the absorption of Gegen. Here, we report an in vivo pharmacokinetic study on rats to explore the effects of soybean milk on the absorption of Gegen and an in vitro Ussing chamber study of puerarin intestinal transmembrane absorption. Area under the plasma concentration-time curve (AUC0–t) and maximum plasma concentration (Cmax) values of puerarin in rats were significantly decreased after drinking soybean milk, when taking Gegen decoction or a Gegen patent medicine (P < 0.01). In the Ussing chamber experiment, cumulative transmission (Qtn) after 2 h and apparent permeability coefficient (Papp) were lower in the puerarin-daidzin and puerarin-soybean milk solution groups than in the puerarin group. Daidzin in soybean milk inhibited the transmembrane transport of puerarin, resulting in decreased bioavailability of puerarin in Gegen. The results of this study strongly suggest that Gegen should not be taken with flavonoid-rich food, particularly soybean products.

Sign in / Sign up

Export Citation Format

Share Document