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Acta Physiologica 2012; Volume 204, Supplement 689
91st Annual Meeting of The German Physiological Society
3/22/2012-3/25/2012
Dresden, Germany
REDUCED BIOAVAILABILITY OF ACETAMINOPHEN AND OF CO-ADMINISTERED SUBSTANCES ACROSS AN INTESTINAL BARRIER MODEL THROUGH DIFFERENT MECHANISMS
Abstract number: P134
Lornejad-Schafer1,2 *M.R., Schafer1,2 C., Rietmuller3 C., Schroder1,2 K.R.
1BioMed-zet Life Science GmbH, zet-LSL, Linz, Austria
2zet-Centre for Alternative and Complementary Methods to Animal Testing, Linz, Austria
3serend-IP GmBH, Mnster, Germany
Question:
Acetaminophen (APAP) or Paracetamol is a widely used drug as pain reliever and fever reducer. Its net intestinal absorption and that of co-administered drugs may be affected by different mechanisms. The aim of this study was to find out how can APAP reduce the bioavailability of different substances across the Caco-2 barrier model?
Methods:
Caco-2 cells seeded onto inserts were differentiated for 21 days, followed by APAP-administration for 24h. The cell transepithelial electrical resistance (TER) and capacitance (Ccl)were analyzed using impedance (Z). The membrane permeability was tested by different-sized molecules: 3–5 kDa and 40 kDa Fluorescein thiocarbamoyl (FITC)-dextran. The activity of the multidrug resistance protein 1 (MRP1/ABCC1) as efflux transporter was tested by rhodamine123. APAP concentration was determined by HPLC analysis. The effect of APAP on the cell membrane topography was investigated using atomic force microscopy (AFM).
Results and Discussion:
APAP increased the membrane integrity, which was measured by two different impedance measuring systems. The increase of TER value (=membrane integrity) correlated significantly with the decreasing permeability of small molecules, FITC-dextran (3–5 kDa). Therefore, we assume that APAP affected the paracellular transport pathway. Besides, APAP decreased cell capacitance dose-dependently. To verify this result, we measured the activity of the efflux transporter MRP1. The transport of its substrate rhodamine 123 and APAP from the basolateral site to the apical site increased significantly after APAP pretreatment. Hence, we assume that APAP induces the MRP1 transporter, which is responsible for the efflux of rhodamine 123 and of APAP from the basolateral site to the apical site. In addition, we recorded cellular surfaces by AFM to visualise a possible impact of APAP on cell membrane topography.
Conclusion:
APAP may reduce the bioavailability of co-administered substances through different mechanisms: changed the cell membrane topography and decreased para- and increased transcellular transport activity in the net intestinal absorption.
Keywords:
Acetaminophen, Atomic Force Microscopy, Impedance, Intestinal Barrier Model, Multidrug Resistance Protein 1 (MRP1)
To cite this abstract, please use the following information:
Acta Physiologica 2012; Volume 204, Supplement 689 :P134