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.
Department of Pharmacy, Uppsala University, Uppsala, Sweden.
Christer
C
Tannergren
Niclas
N
Petri
Lars
L
Knutson
Mikael
M
Hedeland
Ulf
U
Bondesson
Hans
H
Lennernäs
D000328:Adult; D000465:Algorithms; D018926:Anti-Allergic Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007408:Intestinal Absorption / Q000187:drug effects; D007422:Intestines / Q000098:blood supply; D007583:Jejunum / Q000098:blood supply / Q000378:metabolism; D008297:Male; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012039:Regional Blood Flow / Q000502:physiology; D013056:Spectrophotometry, Ultraviolet; D016593:Terfenadine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D014700:Verapamil / Q000494:pharmacology
D018926:Anti-Allergic Agents; D002121:Calcium Channel Blockers; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D016593:Terfenadine; D014700:Verapamil; C093230:fexofenadine