The utility of in vitro trials that use Caco-2 cell systems as a replacement for animal intestinal permeability and human bioequivalence measurements in drug development

• Main Authors: Margarida Estudante, Cristina de Mello-Sampayo, Selma Sahin, José Morais, Leslie Z. Benet
• Format: Article
• Language: English
• Published: ALIES - Associação Lusófona para o Desenvolvimento da Investigação e do Ensino das Ciências da Saúde 2015-04-01
• Series: Journal Biomedical and Biopharmaceutical Research (BBR)
• Subjects: Caco-2; intestinal permeability; P-glycoprotein; diltiazem; verapamil; digoxin
• Online Access: http://www.alies.pt/BBR%20Editions/Vol-12-1-2015/art11_12n1.pdf

Caco-2 cells have been widely used for in vitro intestinal permeability screening of new molecules in drug development but with some pitfalls. Limiting the application of Caco-2 permeability screening to passive compounds is difficult as the majority of approved drugs include both passive diffusion and active transport. The aim of this study was to evaluate Caco-2 cells utility in assessing effects of P-gp mediated efflux. For that purpose the study design included the highly soluble, highly permeable (class 1), verapamil and diltiazem, the highly soluble and poorly permeable drug (class 3) digoxin and the P-gp inhibitor GG918. The apparent permeability and efflux ratio (ER) were calculated. Digoxin, a positive control for P-gp, presented an ER of 4, which decreased to around 1 by GG918 addition, consistent with a P-gp effect in Caco-2 cells. ER for verapamil and diltiazem was nearly 1 and the presence of GG918 resulted in no ERs changes. These results suggest that P-gp apparently plays a minimal role in transport of class 1 drugs across Caco-2 cells while class 3 drugs should be significantly affected by P-gp. It is suggested that Caco-2 cells may be useful to determine whether P-gp plays a relevant role in intestinal absorption.