Acetaminophen inhibits intestinal P-glycoprotein transport activity

NOVAK A; DELLI CARPINI G; RUIZ ML; LUQUITA MG; RUBIO M; MOTTINO AD; GHANEM CI

JOURNAL OF PHARMACEUTICAL SCIENCES

JOHN WILEY & SONS INC

Lugar: New York; Año: 2013 p. 3830 - 3837

0022-3549

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 0ºC, consistet 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 (Ver) 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 to 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 co-administered with AP.