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Updated: Jun 7, 2026
An Intestine/Liver Microphysiological System for Drug Pharmacokinetic and Toxicological Assessment
Published on: December 3, 2020
Acetaminophen-induced stimulation of MDR1 expression and activity in rat intestine and in LS 174T human intestinal
Carolina I Ghanem1, Agostina Arias, Analia Novak
1Instituto de Investigaciones Farmacológicas, Facultad de Farmacia y Bioquímica, CONICET-Universidad de Buenos Aires, Buenos Aires, Argentina. cghanem@ffyb.uba.ar
Abstract:
The well-known analgesic and antipyretic drug N-acetyl-p-aminophenol (acetaminophen; APAP) has been previously reported to affect MDR1 expression in rat liver. In this study, we have investigated the effect of subtoxic doses of APAP on MDR1 expression and activity in rat intestine and human intestinal cells. Administration of APAP at increasing doses of 0.2, 0.3, and 0.6g/kg b.w., i.p. over three consecutive days, induced MDR1 expression in rat duodenum (+240%) and ileum (+160%) as detected by western blotting. This was accompanied by preserved localization of the protein at the surface of the villus, as detected by confocal immunofluorescence microscopy. MDR1 activity was increased by 50% in APAP treated rats, as evaluated by serosal to mucosal secretion of rhodamine 123 in everted intestinal sacs. Treatment with APAP also decreased by 65% the portal vein concentrations of digoxin found in anesthetized rats after intraduodenal administration of this drug, which is consistent with an APAP-induced increased efficacy of intestinal barrier for digoxin net absorption. Exposure of LS 174T human colon adenocarcinoma cells to subtoxic APAP concentration (5mM) induced an increase in MDR1 mRNA expression (+46%), which was accompanied with an enhanced ability (+78%) to reduce intracellular content of rhodamine 123. Taken together these data suggest the existence of APAP-induced stimulation of MDR1 transcription in the intestinal epithelium. These findings are of clinical relevance, as co-administration of APAP with other MDR1 substrates could indirectly inhibit the net intestinal absorption of these drugs, leading to changes in their pharmacokinetics and therapeutic efficacy.
Insights
N-acetyl-p-aminophenol (acetaminophen) increases intestinal MDR1 expression and activity. This impacts drug absorption, potentially altering therapeutic efficacy when co-administered with other MDR1 substrates.
Area of Science:
- Pharmacology
- Gastroenterology
- Molecular Biology
Background:
- N-acetyl-p-aminophenol (acetaminophen) is a common analgesic and antipyretic.
- Previous studies indicated acetaminophen affects MDR1 expression in rat liver.
Purpose of the Study:
- To investigate the effect of subtoxic acetaminophen doses on MDR1 expression and activity in the rat and human intestine.
- To determine the clinical relevance of acetaminophen's impact on intestinal drug absorption.
Main Methods:
- Western blotting and confocal immunofluorescence microscopy to detect MDR1 expression and localization in rat duodenum and ileum.
- Everted intestinal sacs to measure MDR1 activity via rhodamine 123 secretion.
- Intraduodenal digoxin administration in rats to assess acetaminophen's effect on net absorption.
- Exposure of LS 174T human colon cells to acetaminophen to evaluate MDR1 mRNA expression and rhodamine 123 intracellular content.
Main Results:
- Acetaminophen (APAP) significantly increased MDR1 expression in rat duodenum (+240%) and ileum (+160%).
- MDR1 activity increased by 50% in APAP-treated rats, enhancing intestinal barrier function for digoxin.
- In human colon cells, APAP increased MDR1 mRNA expression (+46%) and rhodamine 123 efflux (+78%).
Conclusions:
- Subtoxic doses of acetaminophen stimulate MDR1 transcription and activity in the intestinal epithelium.
- Co-administration of acetaminophen with MDR1 substrates may inhibit their net intestinal absorption.
- These findings have clinical implications for drug pharmacokinetics and therapeutic efficacy.
