A catch-up validation study on reconstructed human epidermis (SkinEthic RHE) for full replacement of the Draize skin irritation test.

Efforts to fully replace the in vivo Draize skin irritation test, according to the Directive 67/548/ECC or OECD TG 404, were reinforced with the seventh Amendment of the Cosmetic Directive and the REACh regulation. In 2007, the EpiSkin test method was scientifically validated and recognized as the stand alone method to discriminate skin irritants (R38) from non-irritants (no label) according to the definition of the EU risk phrases. An ECVAM performance standards (PS) document was defined to evaluate the accuracy and reliability of other analogous test methods (ECVAM SIVS, May 2007).

Experimental estimation of the role of P-Glycoprotein in the pharmacokinetic behaviour of telithromycin, a novel ketolide, in comparison with roxithromycin and other macrolides using the Caco-2 cell model.

Purpose: The aim of this study was to examine the transport mechanism of telithromycin in comparison with erythromycin, azithromycin, clarithromycin and roxithromycin.

Methods: These antibiotics were examined in Caco-2 cell monolayers in order to demonstrate the potential involvement of P-GP in the absorption process, using verapamil as a P-GP competitor. A model using concentration equilibrium conditions was developed to delineate passive and active permeability components of telithromycin and roxithromycin transport in order to predict absorption in humans.

HT29-MTX and Caco-2/TC7 monolayers as predictive models for human intestinal absorption: role of the mucus layer.

The permeability of 19 compounds in both the Caco-2/TC7 and HT29-MTX models was determined, and the ability of each model to predict intestinal absorption in humans was compared. Similar apparent permeability values (log P(app)) were obtained in both models for the majority of compounds tested, and plots of log P(app) versus fraction absorbed in humans gave comparable sigmoidal curves. A linear correlation was also observed between the log P(app) values derived from these two models, which suggests that HT29-MTX is an alternative model for absorption prediction in humans.

Absorption of angiotensin II antagonists in Ussing chambers, Caco-2, perfused jejunum loop and in vivo: importance of drug ionisation in the in vitro prediction of in vivo absorption.

The aims of this study were (i) to compare the absorption of three closely related inhibitors of angiotensin II, RU60018, RU60079 and HR720, in various in vitro and in vivo models, and (ii) to explain the differences in the results and to assess the importance of drug ionisation to predict absorption. Drug absorption was investigated in Ussing chambers, Caco-2 cell monolayers, perfused rat jejunum loops and in vivo after oral, intraduodenal or intravenous administration. In Ussing chambers, the analogues showed the same site-related absorption profile and a common mechanism involving the paracellular pathway.