Acetaminophen inhibits intestinal p-glycoprotein transport activity
| Autor: | Griselda Delli Carpini, Modesto C. Rubio, Aldo D. Mottino, María Laura Ruiz, Analia Novak, Carolina Inés Ghanem, Marcelo G. Luquita |
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| Rok vydání: | 2013 |
| Předmět: |
Male
Digoxin Enterocyte Pharmaceutical Science Biological Transport Active Cyclosporins Pharmacology Rhodamine 123 Intestinal absorption Permeability chemistry.chemical_compound Non-competitive inhibition Cell Line Tumor medicine Animals Humans ATP Binding Cassette Transporter Subfamily B Member 1 Intestinal Mucosa Rats Wistar P-glycoprotein Acetaminophen biology Chemistry Hep G2 Cells Apical membrane Rats Intestines medicine.anatomical_structure Enterocytes Intestinal Absorption Verapamil Paracellular transport biology.protein medicine.drug |
| Zdroj: | Journal of pharmaceutical sciences. 102(10) |
| ISSN: | 1520-6017 |
| Popis: | Repeated acetaminophen (AP) administration modulates intestinal P-glycoprotein (P-gp) expression. Whether AP can modulate P-gp activity in a short-term fashion is unknown. We investigated the acute effect of AP on rat intestinal P-gp activity in vivo and in vitro. In everted intestinal sacs, AP inhibited serosal-mucosal transport of rhodamine 123 (R123), a prototypical P-gp substrate. R123 efflux plotted against R123 concentration adjusted well to a sigmoidal curve. Vmax decreased 50% in the presence of AP, with no modification in EC50, or slope, ruling out the possibility of inhibition to be competitive. Inhibition by AP was absent at 0°C, consistent with interference of the active transport of R123 by AP. Additionally, AP showed no effect on normal localization of P-gp at the apical membrane of the enterocyte and neither affected paracellular permeability. Consistent with absence of a competitive inhibition, two further strategies strongly suggested that AP is not a P-gp substrate. First, serosal-mucosal transport of AP was not affected by the classical P-gp inhibitors verapamil or Psc 833. Second, AP accumulation was not different between P-gp knock-down and wild-type HepG2 cells. In vivo intestinal absorption of digoxin, another substrate of P-gp, was assessed in the presence or absence of AP (100 μM). Portal digoxin concentration was increased by 214%, in average, by AP, as compared with digoxin alone. In conclusion, AP inhibited P-gp activity, increasing intestinal absorption of digoxin, a prototypical substrate. These results suggest that therapeutic efficacy of P-gp substrates can be altered if coadministered with AP. |
| Databáze: | OpenAIRE |
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