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  • 1
    Electronic Resource
    Electronic Resource
    Characterization of the Unstirred Water Layer in Caco-2 Cell Monolayers Using a Novel Diffusion Apparatus (1991)
    Springer
    Pharmaceutical research 8 (1991), S. 222-227 
    Details
    ISSN: 1573-904X
    Keywords: Caco-2 ; unstirred water layer ; intestinal permeability ; steroids ; cell culture
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Caco-2 monolayers grown on Transwell polycarbonate membranes have been characterized as a valuable tool in drug transport studies. Despite the clear advantages of this system, the lack of stirring may create an unstirred water layer (UWL) whose resistance may limit the transcellular transport of lipophilic molecules. The objective of this study was to evaluate a novel diffusion cell where the transport buffer is mixed by gas lift and to determine the mixing flow rate needed to reduce the thickness (h) of the UWL adjacent to cell monolayers. The transport of the leakage marker, mannitol, remained at least 15-fold lower than the flux of testosterone, indicating that the stirring flow rates used did not affect the integrity of the monolayers. The permeability (P) of testosterone (log PC 3.13) across monolayers mounted on this diffusion cell was 4.07, 10.90, and 14.18 × 10−5 cm/sec at flow rates of 0, 15, and 40 ml/min, respectively, and the apparent UWLs were calculated to be 1966, 733, and 564µm. P and h in the stagnant Transwell were 3.08 × 10−5 cm/sec and 2597 µm, respectively. On the other hand, h was significantly smaller in the unstirred, cell-free membranes than in their cell-containing counterparts. P was correlated with lipophilicity and, in the case of the more lipophilic compounds, with the mixing flow rate.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015848205447
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  • 2
    Electronic Resource
    Electronic Resource
    Structural Requirements for Interaction with the Oligopeptide Transporter in Caco-2 Cells (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 317-319 
    Details
    ISSN: 1573-904X
    Keywords: oligopeptide transporter ; structure-transport ; Caco-2 ; dipeptides ; cephalexin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016259816661
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  • 3
    Electronic Resource
    Electronic Resource
    The Use of Cultured Epithelial and Endothelial Cells for Drug Transport and Metabolism Studies (1990)
    Springer
    Pharmaceutical research 7 (1990), S. 435-451 
    Details
    ISSN: 1573-904X
    Keywords: epithelial cell cultures ; endothelial cell cultures ; transport of drugs ; cell culture ; cell culture, intestinal, rectal, buccal, sublingual, nasal, ophthalmic
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract In an effort to develop novel strategies for delivery of drug candidates arising from rational drug design and recombinant DNA technology, pharmaceutical scientists have begun to employ the techniques of cell culture to study drug transport and metabolism at specific biological barriers. This review describes some of the general factors that should be considered in developing a cell culture model for transport studies and metabolism studies. In addition, we review in detail the recent progress that has been made in establishing, validating, and using cell cultures of epithelial barriers (e.g., cells that constitute the intestinal, rectal, buccal, sublingual, nasal, and ophthalmic mucosa as well as the epidermis of the skin) and the endothelial barriers (e.g., brain microvessel endothelial cells).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015800312910
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  • 4
    Electronic Resource
    Electronic Resource
    Interplay Between CYP3A-Mediated Metabolism and Polarized Efflux of Terfenadine and Its Metabolites in Intestinal Epithelial Caco-2 (TC7) Cell Monolayers (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 625-632 
    Details
    ISSN: 1573-904X
    Keywords: TC7 ; Caco-2 ; cytochrome P450 ; CYP3A ; terfenadine ; intestinal metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To further characterize cytochrome P450 (CYP) and P-glyco-protein (Pgp) expression in monolayers of the Caco-2 cell clone TC7, a cell culture model of the human intestinal epithelium. To study the interplay between CYP3A and Pgp as barriers to intestinal drug absorption in TC7 cells using terfenadine and its metabolites as substrates. Methods. mRNA expression of eight CYPs and Pgp was investigated in TC7 and parental Caco-2 (Caco-2p) cell monolayers using RT-PCR. The CYP3A kinetics was determined in microsomes from both cell lines. The transport, metabolism and efflux of terfenadine and its metabolites were investigated in TC7 monolayers. Results. Both TC7 and Caco-2p cells expressed mRNA for Pgp and several important CYPs. However, mRNA for CYP3A4 was detectable only from TC7 cells. The relative affinity of CYP3A for terfenadine metabolism in the two cell lines was comparable, but the maximum reaction rate in the TC7 cells was 8-fold higher. The rate of transport of terfenadine and its metabolites hydroxy-terfenadine (HO-T) and azacyclonol across TC7 monolayers was 7.1-, 3.5- and 2.1-fold higher, respectively, in the basolateral to apical direction than it was in the apical to basolateral (AP-BL) direction. Inhibition studies indicated that the efflux was mediated by Pgp. Ketoconazole increased the AP-BL transport terfenadine dramatically by inhibiting both terfenadine metabolism and Pgp efflux. Conclusions. Cell culture models such as TC7 provide qualitative information on drug interactions involving intestinal CYP3A and Pgp.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018851919674
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  • 5
    Electronic Resource
    Electronic Resource
    Comparison of CYP3A Activities in a Subclone of Caco-2 Cells (TC7) and Human Intestine (1997)
    Springer
    Pharmaceutical research 14 (1997), S. 1019-1025 
    Details
    ISSN: 1573-904X
    Keywords: TC7 ; Caco-2 ; CYP3A ; terfenadine ; intestinal metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To compare the activity of the CYP3A enzyme expressed by TC7, a cell culture model of the intestinal epithelial cell, to the activity of human intestinal CYP3A4, using terfenadine as a substrate. Methods. The metabolism of terfenadine was investigated in intact cells and microsomal preparations from TC7, human intestine, and liver. The effect of two CYP3A inhibitors, ketoconazole and troleandomycin (TAO), on the metabolism of terfenadine was also examined. Results. Only hydroxy-terfenadine was detected in TC7 microsomal incubations. In contrast, azacyclonol and hydroxy-terfenadine were detected in human intestinal and hepatic microsomal incubations. The Km values for hydroxy-terfenadine formation in TC7 cells, intestine and liver microsomes were 1.91, 2.5, and 1.8, μM respectively. The corresponding Vmax values were 2.11, 61.0, and 370 pmol/min/mg protein. Km values for azacyclonol in intestinal and hepatic samples were 1.44 and 0.82 μM and the corresponding Vmax values were 14 and 60 pmol/min/mg protein. The formation of hydroxy-terfenadine was inhibited by ketoconazole and TAO in human intestine and TC7 cell microsomes. The Km and Vmax values for terfenadine metabolism in intact TC7 cells were similar to those from TC7 cell microsomes. Conclusions. Our results indicate that TC7 cells are a potentially useful alternative model for studies of CYP3A mediated drug metabolism. The CYP3A expressed by TC7 cells is not CYP3A4, but probably CYP3A5, making this cell line suitable for studies of colonic drug transport and metabolism.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1012197110917
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