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Human enteroid monolayers as a potential alternative for Ussing chamber and Caco-2 monolayers to study passive permeability and drug efflux. | LitMetric

Human enteroid monolayers as a potential alternative for Ussing chamber and Caco-2 monolayers to study passive permeability and drug efflux.

Eur J Pharm Sci

Division of Pharmacology and Toxicology, Department of Pharmacy, Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen (Route 137), Nijmegen, the Netherlands; Department of Intensive Care, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Neonatal and Pediatric Intensive Care, Erasmus MC Sophia Children's Hospital, Rotterdam, the Netherlands. Electronic address:

Published: October 2024

AI Article Synopsis

  • - The intestine plays a crucial role in drug absorption and bioavailability, impacting drug efficacy and safety, but current in vitro models often don't accurately represent human intestinal barriers.
  • - This study investigates human enteroid monolayers as a potential alternative for studying intestinal drug absorption by comparing them to primary tissue (Ussing chamber) and Caco-2 cells through various transport studies and RNA sequencing.
  • - All three models demonstrated functional efflux transport mechanisms, with enteroid monolayers showing unique gene expression patterns, making them a promising experimental platform alongside existing models for better understanding drug absorption.

Article Abstract

After oral administration, the intestine is the first site of drug absorption, making it a key determinant of the bioavailability of a drug, and hence drug efficacy and safety. Existing non-clinical models of the intestinal barrier in vitro often fail to mimic the barrier and absorption of the human intestine. We explore if human enteroid monolayers are a suitable tool for intestinal absorption studies compared to primary tissue (Ussing chamber) and Caco-2 cells. Bidirectional drug transport was determined in enteroid monolayers, fresh tissue (Ussing chamber methodology) and Caco-2 cells. Apparent permeability (P) and efflux ratios for enalaprilat (paracellular), propranolol (transcellular), talinolol (P-glycoprotein (P-gp)) and rosuvastatin (Breast cancer resistance protein (BCRP)) were determined and compared between all three methodologies and across intestinal regions. Bulk RNA sequencing was performed to compare gene expression between enteroid monolayers and primary tissue. All three models showed functional efflux transport by P-gp and BCRP with higher basolateral to apical (B-to-A) transport compared to apical-to-basolateral (A-to-B). B-to-A P values were similar for talinolol and rosuvastatin in tissue and enteroids. Paracellular transport of enalaprilat was lower and transcellular transport of propranolol was higher in enteroids compared to tissue. Enteroids appeared show more region- specific gene expression compared to tissue. Fresh tissue and enteroid monolayers both show active efflux by P-gp and BCRP in jejunum and ileum. Hence, the use of enteroid monolayers represents a promising and versatile experimental platform to complement current in vitro models.

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Source
http://dx.doi.org/10.1016/j.ejps.2024.106877DOI Listing

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