Acetaminophen (AP) inhibits intestinal P-glycoprotein (P-gp) activity in vitro and in vivo.

NOVAK, A.; DELLI CARPINI G.; RUIZ,M.L.; LUQUITA,M.G.; MODESTO, C.R.; MOTTINO,A.D; GHANEM C.I

Boston

Congreso; Experimental Biology 2013; 2013

American society of Pharmaceutical and Experimental Therapeutic

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.