Abstract

The Caco-2 model is a well-accepted in vitro model for the estimation of fraction absorbed in human intestine. Due to the lack of cytochrome P450 3A4 (CYP3A4) activities, Caco-2 model is not suitable for the investigation of intestinal first-pass metabolism. The purpose of this study is to evaluate a new human intestine model, EpiIntestinal microtissues, as a tool for the prediction of oral absorption and metabolism of drugs in human intestine. The activities of relevant drug transporters and drug metabolizing enzymes, including MDR1 P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), CYP3A4, CYP2J2, UDP-glucuronosyltransferases (UGT), carboxylesterases (CES), etc., were detected in functional assays with selective substrates and inhibitors. Compared to Caco-2, EpiIntestinal microtissues proved to be a more holistic model for the investigation of drug absorption and metabolism in human gastrointestinal tract.

Highlights

  • Despite the recent innovations in drug delivery, oral administration remains the major route of drug administration

  • A number of drug metabolizing enzymes (DME) have been identified in Caco-2 cells, including UDP glucuronosyltransferases (UGT) [3] and carboxylesterases (CES) [4], cytochrome P450 3A4 (CYP3A4), the major drug metabolizing enzyme in human intestine and liver is missing in Caco-2 cells [5]

  • At the concentration of 10 μM used by Ayehunie et al, a strong inhibition of both breast cancer resistance protein (BCRP) and P-gp can be expected

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Summary

Introduction

Despite the recent innovations in drug delivery, oral administration remains the major route of drug administration. A number of drug metabolizing enzymes (DME) have been identified in Caco-2 cells, including UDP glucuronosyltransferases (UGT) [3] and carboxylesterases (CES) [4], cytochrome P450 3A4 (CYP3A4), the major drug metabolizing enzyme in human intestine and liver is missing in Caco-2 cells [5]. Sections of human intestinal tissue or mucosal biopsy mounted in Ussing chamber can be used to study drug absorption and metabolism in human intestine [6]. The advantage of this method is the combined measurement of permeability/active transport and metabolism.

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