Enantioselective uptake of fexofenadine by Caco-2 cells as model intestinal epithelial cells

Objectives  Fexofenadine contains a chiral carbon in its chemical structure and is orally administered as a racemic mixture. This study evaluated the selective uptake of fexofenadine enantiomers by Caco-2 cells as a model of intestinal epithelial cells. Methods  R(+)-fexofenadine or S(−)-fexofenadine was applied to Caco-2 cells, followed by incubation. After incubation, the amounts of fexofenadine enantiomers in cells were determined. The kinetic parameters for the uptake of fexofenadine enantiomers by Caco-2 cells were estimated using the Michaelis–Menten equation. Key findings  The transporter-mediated uptake rate of R(+)-fexofenadine was 1.7-fold higher than that of S(−)-fexofenadine. The difference in transporter-mediated R(+)-fexofenadine and S(−)-fexofenadine uptake was completely diminished under ATP-depleted conditions and in the presence of organic anion transporter peptide (OATP) inhibitors. Also, a Dixon plot showed that each fexofenadine enantiomer was competitively inhibited by the other enantiomer. The ratio of R(+)-fexofenadine uptake to S(−)-fexofenadine uptake in the case of a racemic mixture was higher than that in the case of a single enantiomer. Conclusion  This study suggested that the selective absorption of fexofenadine enantiomers by intestinal epithelial cells might have been due to the selective uptake mediated by OATPs and that the difference in intestinal absorption was enhanced with a racemic mixture.