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Application of a Modified In Situ Perfusion Model to Quantify Intestinal Drug Excretion and Transporter-Mediated
Rongjin Sun1, Li Li1, Lu Wang1
1Department of Pharmacological and Pharmaceutical Science, College of Pharmacy, University of Houston, 4349 Martin Luther King Blvd, Houston, Texas, 77204, USA.
The AAPS Journal
|March 12, 2026
Summary
Intestinal excretion is a key drug elimination pathway, especially for apixaban. Inhibiting intestinal efflux transporters like P-gp and Mrp2 significantly impacts apixaban clearance and systemic exposure.
Area of Science:
- Pharmacokinetics
- Drug Metabolism and Elimination
- Gastrointestinal Pharmacology
Background:
- Intestinal excretion (IE) is an understudied drug elimination route and a site for drug-drug interactions (DDIs).
- Understanding IE is crucial for predicting drug behavior and interactions.
- Apixaban, talinolol, and irinotecan were selected to investigate IE mechanisms.
Purpose of the Study:
- To characterize the intestinal clearance (CLint) of apixaban, talinolol, and irinotecan using a modified rat in situ intestinal perfusion model.
- To evaluate the impact of specific efflux transporter inhibitors (P-gp, Mrp2, Bcrp) on the IE, systemic exposure, and metabolite ratios of these drugs.
- To assess the role of IE as an elimination pathway and its potential for DDIs.
Main Methods:
- Utilized a modified rat in situ intestinal perfusion model for short-term drug recovery studies.
- Administered drugs via constant-rate intravenous infusion over 2.5 hours.
- Investigated the effects of P-gp inhibitor elacridar, Mrp2 inhibitor MK571, and Bcrp inhibitor KO143 on drug disposition.
Main Results:
- Intestinal excretion significantly contributes to apixaban elimination (36%), but plays a minor role for talinolol (11%) and irinotecan (22%).
- Inhibition of P-gp/Mrp2 transporters markedly reduced apixaban's CLint, increasing its systemic exposure (AUC), without affecting biliary excretion or metabolite ratio.
- Systemic pharmacokinetics of talinolol and irinotecan remained unaltered, likely due to their limited IE.
- IE was found to be temperature- and dose-dependent, but not segment-dependent.
Conclusions:
- Intestinal excretion is a critical elimination pathway, particularly for apixaban, and a significant site for transporter-mediated DDIs.
- The modified perfusion model is a valuable tool for characterizing CLint and assessing transporter interactions.
- Apixaban serves as a suitable reference drug for studying intestinal clearance inhibition.
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