Biorelevant media for transport experiments in the Caco-2 model to evaluate drug absorption in the fasted and the fed state and their usefulness
| Autor: | Constantinos Markopoulos, M. Symillides, Christos Reppas, Maria Vertzoni, Georgios Imanidis, F Thoenen, Daniel Preisig, Neil Parrott |
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| Rok vydání: | 2013 |
| Předmět: |
Physiologically based pharmacokinetic modelling
Drug Evaluation Preclinical Pharmaceutical Science digestive system Intestinal absorption medicine Humans Chromatography Aqueous solution Chemistry digestive oral and skin physiology Biological Transport General Medicine Fasting Permeation Postprandial Period Small intestine Body Fluids medicine.anatomical_structure Intestinal Absorption Caco-2 Culture Media Conditioned Lipophilicity Caco-2 Cells Biotechnology Federal state |
| Zdroj: | European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V. 86(3) |
| ISSN: | 1873-3441 |
| Popis: | In this work we developed and characterized transport media that simulate the composition of micellar phase of intestinal fluids in the fasted and, especially, in the fed state and are appropriate for evaluating intestinal drug permeability characteristics using the Caco-2 model (FaSSIF-TM(Caco) and FeSSIF-TM(Caco), respectively). Media composition was based on FaSSIF-V2 and FeSSIF-V2 and recently reported data on total lipid concentrations in the micellar phase of contents of the upper small intestine in the fasted and the fed state and was adapted for cell culture compatibility. Permeation data were evaluated by compartmental kinetic modeling. Permeability coefficients, P, of hydrophilic drugs were not affected by media composition. In contrast, P values of a series of lipophilic compounds measured with FaSSIF-TM(Caco) and FeSSIF-TM(Caco), and reflecting transport by diffusion were smaller than those obtained with a purely aqueous reference transport medium, aq-TM(Caco), following the rank order aq-TM(Caco)>FaSSIF-TM(Caco)>FeSSIF-TM(Caco). The decline of permeability values was stronger as lipophilicity of the compounds increased. Compared with values estimated using aq-TM(Caco), permeability was reduced, depending on the compound, by more than 20- to 100-fold when measured with FeSSIF-TM(Caco) whereas compound ranking in regard to the permeability characteristics was also affected. The impact of reduced P value on flux through the mucosa, hence on drug absorption, in combination with the drug amount loaded on colloidal particles needs to be taken into consideration in PBPK modeling especially when the food effect is evaluated. |
| Databáze: | OpenAIRE |
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