Drug Transport across Porcine Intestine Using an Ussing Chamber System: Regional Differences and the Effect of P-Glycoprotein and CYP3A4 Activity on Drug Absorption.

Yogeshvar Kalia,Yvonne Arnold,Julien Thorens,Stéphane Bernard

doi:10.3390/pharmaceutics11030139

Yogeshvar Kalia, Yvonne Arnold + Show 2 more

Open Access

https://doi.org/10.3390/pharmaceutics11030139

Copy DOI

Abstract

Drug absorption across viable porcine intestines was investigated using an Ussing chamber system. The apparent permeability coefficients, Papp,pig, were compared to the permeability coefficients determined in humans in vivo, Peff,human. Eleven drugs from the different Biopharmaceutical Classification System (BCS) categories absorbed by passive diffusion with published Peff,human values were used to test the system. The initial experiments measured Papp,pig for each drug after application in a Krebs–Bicarbonate Ringer (KBR) buffer and in biorelevant media FaSSIF V2 and FeSSIF V2, mimicking fasted and fed states. Strong sigmoidal correlations were observed between Peff,human and Papp,pig. Differences in the segmental Papp,pig of antipyrine, cimetidine and metoprolol confirmed the discrimination between drug uptake in the duodenum, jejunum and ileum (and colon); the results were in good agreement with human data in vivo. The presence of the P-gp inhibitor verapamil significantly increased Papp,pig across the ileum of the P-gp substrates cimetidine and ranitidine (p < 0.05). Clotrimazole, a potent CYP3A4 inhibitor, significantly increased Papp,pig of the CYP3A4 substrates midazolam, verapamil and tamoxifen and significantly decreased the formation of their main metabolites. In conclusion, the results showed that this is a robust technique to predict passive drug permeability under fasted and fed states, to identify regional differences in drug permeability and to demonstrate the activity of P-gp and CYP3A4.

Highlights

Methods to predict intestinal drug absorption in humans in vivo range from purely in silico computational techniques to preclinical animal studies in vivo
This was done by determining the Papp,pig of 11 drugs from the four Biopharmaceutical Classification System (BCS) categories formulated in Krebs–Bicarbonate Ringer (KBR) and in FaSSIF V2 and FeSSIF V2 followed by a comparison to the Peff,human reported in the literature (Tables 1 and 2)
The ability to use biorelevant media that simulate more physiological conditions is a major advantage of this system since it enables a better approximation of the food effects on drug permeation [71]; this can be difficult with Caco-2 cells due to the cytotoxic effects [72]

Summary

Introduction

Methods to predict intestinal drug absorption in humans in vivo range from purely in silico computational techniques to preclinical animal studies in vivo. The monolayer cell culture system is limited by the absence of a full physiological membrane and the specific properties of the individual cell types present in the different segments of the intestine. These models are usually used to evaluate the permeability of the API alone since they are not sufficiently robust to support either biorelevant media or “real” formulations. In vivo studies cannot necessarily provide insight into regional differences in drug absorption, this has been attempted to be addressed in rats by the single-pass intestinal perfusion technique or, with appropriate adjustments, the closed-loop Doluisio method [14]

Objectives

Methods

Results

Conclusion