title: Acetaminophen inhibits intestinal p-glycoprotein transport activity.
abstract: 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.
authors.affiliation: Cátedra de Fisiopatología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Analia
authors.initials: A
authors.lastname: Novak
authors.forename: Griselda Delli
authors.initials: GD
authors.lastname: Carpini
authors.forename: María Laura
authors.initials: ML
authors.lastname: Ruiz
authors.forename: Marcelo G
authors.initials: MG
authors.lastname: Luquita
authors.forename: Modesto C
authors.initials: MC
authors.lastname: Rubio
authors.forename: Aldo D
authors.initials: AD
authors.lastname: Mottino
authors.forename: Carolina I
authors.initials: CI
authors.lastname: Ghanem
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000082:Acetaminophen / Q000494:pharmacology*; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects*; D045744:Cell Line, Tumor; D003524:Cyclosporins / Q000494:pharmacology; D004077:Digoxin / Q000494:pharmacology; D020895:Enterocytes / Q000187:drug effects / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D007422:Intestines / Q000187:drug effects*; D008297:Male; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D020112:Rhodamine 123 / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003524:Cyclosporins; D020112:Rhodamine 123; D000082:Acetaminophen; D004077:Digoxin; D014700:Verapamil; C070272:valspodar
keywords: ABC transporters; MDR1; P-glycoprotein; acetaminophen; digoxin; drug interactions; intestinal absorption; intestine; multidrug resistance; sigmoidal