Multiple transport mechanisms involved in the intestinal absorption and first-pass extraction of fexofenadine.

OBJECTIVE: Our objective was to investigate the main in vivo transport mechanisms of fexofenadine involved in the intestinal absorption and bioavailability of the drug in humans.
METHODS: A jejunal single-pass perfusion study was performed in 10 healthy volunteers. Each experiment lasted for 200 minutes and was divided into 2 periods of 100 minutes. During the control period (0-100 minutes), the jejunal segment was perfused with 100 mg/L (186-micromol/L) fexofenadine. In the treatment period (100-200 minutes), fexofenadine was coperfused with 500 mg/L (1018-micromol/L) of the membrane transport inhibitor verapamil. The concentrations of fexofenadine in the perfusate and plasma were measured by HPLC with ultraviolet and mass detection, respectively.
RESULTS: Verapamil did not significantly affect the human effective jejunal permeability of fexofenadine. The mean (+/-SD) effective jejunal permeability values were 0.06 +/- 0.07. 10(-4) cm/s and 0.04 +/- 0.07. 10(-4) cm/s in the control and treatment periods, respectively. However, verapamil increased the apparent absorption rate constant into the systemic circulation and the area under the plasma concentration-time curve for fexofenadine from 0.0030 +/- 0.0012 min(-1) to 0.0255 +/- 0.0103 min(-1) (P <.001) and from 161 +/- 181 ng/mL x min to 664 +/- 537 ng/mL x min (P <.01), respectively.
CONCLUSIONS: In this in vivo perfusion study verapamil increased the bioavailability of fexofenadine. Because the permeability, which is a direct measure of intestinal transport, was unchanged, we suggest that the major reason for this effect was decreased first-pass liver extraction of fexofenadine. The most plausible mechanism is either decreased organic anion transporting polypeptide-mediated sinusoidal uptake or P-glycoprotein-mediated canalicular secretion of fexofenadine, or both.