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
Summary
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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