Transport characteristics of fexofenadine in the Caco-2 cell model.
OBJECTIVE
To investigate the membrane transport mechanisms of fexofenadine in the Caco-2 model.


METHODS
Transport studies were performed in Caco-2 cell monolayers 21-25 days after seeding. The apparent permeability (Papp) of fexofenadine was determined in the concentration range 10-1000 microM in the basolateral-to-apical (b-a) and 50-1000 microM in the apical-to-basolateral (a-b) direction. The concentration-dependent effects of various inhibitors of P-glycoprotein (P-gp) (GF120918, ketoconazole, verapamil, erythromycin), multidrug resistant associated protein (MRP) (indomethacin, probenecid), and organic anion transporting polypeptide (OATP) (rifamycin SV) on the bidirectional transport of 150 microM fexofenadine were also examined.


RESULTS
Fexofenadine displayed polarized transport, with the Pappb-a being 28- to 85-fold higher than the Papp(a-b). The Papp(a-b) was independent of the concentration applied, whereas Pappb-a decreased with increasing concentration (Vmax = 5.21 nmol cm(-2)s(-1) and K(M) = 150 microM), suggesting saturation of an apical efflux transporter. All four P-gp inhibitors had a strong, concentration-dependent effect on the Papp of fexofenadine in both directions, with GF 120918 being the most specific among them. The IC50 of verapamil was 8.44 microM on the P-gp-mediated secretion of fexofenadine. The inhibitors of OATP or MRP appeared not to affect the Papp(a-b) of fexofenadine in the Caco-2 model.


CONCLUSIONS
This study clearly indicates that P-gp was the main transport protein of fexofenadine in the Caco-2 model. Even though P-gp was completely inhibited, fexofenadine was predicted to have a low fraction dose absorbed in humans due to poor intestinal permeability, and low passive diffusion seems to be the major absorption mechanism.
Petri
Niclas
N
Department of Pharmacy, Biopharmaceutics Research Group, Uppsala University, S-751 23 Uppsala, Sweden.
Tannergren
Christer
C
Rungstad
David
D
Lennernäs
Hans
H
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors*; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004058:Diffusion; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors; D010539:Permeability; D016593:Terfenadine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*
D018435:ATP Binding Cassette Transporter, Subfamily B; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; D016593:Terfenadine; C093230:fexofenadine