5-Fluorouracil treatment alters the expression of intestinal transporters in rats

Area of Science:

• Pharmacology
• Gastroenterology
• Drug Metabolism

Background:

• 5-Fluorouracil (5-FU) is a critical anticancer agent with known gastrointestinal toxicity.
• This toxicity can potentially disrupt the absorption of orally administered drugs.
• Intestinal transporters, including P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and peptide transporter 1 (PEPT1), play a vital role in drug absorption and disposition.

Purpose of the Study:

• To quantitatively assess the impact of 5-FU-induced intestinal damage on the expression of P-gp, BCRP, and PEPT1 in rats.
• To investigate the functional consequences of altered transporter expression on the absorption of a P-gp substrate.

Main Methods:

• Rats were administered 5-FU orally for five days to induce intestinal damage.
• mRNA and protein expression levels of P-gp, BCRP, and PEPT1 were quantified in different intestinal segments using qRT-PCR and Western blotting.
• The uptake of digoxin, a P-gp substrate, was measured in an everted sac model.

Main Results:

• 5-FU treatment significantly upregulated P-gp and BCRP protein levels in the upper intestinal segment (15-fold and 2.6-fold increase, respectively).
• PEPT1 expression was elevated across most intestinal segments following 5-FU administration.
• Digoxin uptake was significantly reduced in the upper intestinal segments of 5-FU-treated rats, correlating with increased P-gp levels.

Conclusions:

• 5-FU-induced intestinal damage alters the expression of key intestinal transporters, with notable changes in the upper intestine.
• The observed alterations in P-gp, BCRP, and PEPT1 expression can significantly affect the absorption of orally administered drugs.
• These findings highlight the potential clinical implications for drug-drug interactions and therapeutic efficacy in cancer patients receiving 5-FU.