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Acetaminophen (AP) inhibits intestinal P‐glycoprotein (P‐gp) activity in vitro and in vivo.
Author(s) -
Novak Analía,
Carpini Griselda Delli,
Ruiz María Laura,
Luquita Marcelo,
Rubio Modesto Carlos,
Mottino Aldo Domingo,
Ghanem Carolina Inés
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.891.4
Subject(s) - in vivo , rhodamine 123 , p glycoprotein , chemistry , in vitro , pharmacology , medicine , biology , biochemistry , multiple drug resistance , antibiotics , microbiology and biotechnology
AP induces long‐term regulation of expression of intestinal P‐gp. Whether it can acutely modulate P‐gp activity is unknown. Aims To study the effect of AP on rat intestinal P‐gp activity in vivo and in vitro. M&M In vitro. Intestinal everted sacs were filled with rhodamine 123 (serosal), a tipical P‐gp substrate, (R123; 4.5; 9; 12; 18 or 36 μM) and incubated in KH buffer (mucosal) alone or with AP (100 μM), and secretion of R123 was assessed along a 40‐min period. Serosal‐mucosal transport of AP was studied in a similar fashion, in the presence/absence of Psc 833 (10 μM), a specific inhibitor of P‐gp. Transport of AP (10 μM) was also evaluated in P‐gp knock down HepG2 cells. In vivo. Intestinal absorption of digoxin (Dig, 25.6 nmol/kg) was studied by portal vein sampling (30–min period) in the presence or absence of AP (100 μM). Results R123 transport adjusted well to a sigmoideal curve. Its Vmax was decreased by AP (P<0.05), with no modification in EC50 or slope. AP transport was not affected by PSC 833 or by knocking down P‐gp. In vivo intestinal absorption of Dig was increased (+214%) by AP (P<0.05). Conclusion AP inhibited P‐gp activity in vitro and in vivo. AP‐induced changes in Vmax of R123 transport, together with lack of AP transport by P‐gp, suggest that inhibition is unlikely competitive. Bioavailability and therapeutic efficacy of drugs, substrates of P‐gp, can be altered when they are co‐administered with AP.