Document Detail

Multiple transport mechanisms involved in the intestinal absorption and first-pass extraction of fexofenadine.
MedLine Citation:
PMID:  14586383     Owner:  NLM     Status:  MEDLINE    
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.
Christer Tannergren; Niclas Petri; Lars Knutson; Mikael Hedeland; Ulf Bondesson; Hans Lennernäs
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Publication Detail:
Type:  Clinical Trial; In Vitro; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Clinical pharmacology and therapeutics     Volume:  74     ISSN:  0009-9236     ISO Abbreviation:  Clin. Pharmacol. Ther.     Publication Date:  2003 Nov 
Date Detail:
Created Date:  2003-10-30     Completed Date:  2003-11-21     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0372741     Medline TA:  Clin Pharmacol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  423-36     Citation Subset:  AIM; IM    
Department of Pharmacy, Uppsala University, Uppsala, Sweden.
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MeSH Terms
Anti-Allergic Agents / pharmacokinetics*
Area Under Curve
Biological Availability
Calcium Channel Blockers / pharmacology
Chromatography, High Pressure Liquid
Intestinal Absorption* / drug effects
Intestines / blood supply
Jejunum / blood supply,  metabolism
Membrane Transport Modulators
Membrane Transport Proteins / antagonists & inhibitors,  metabolism*
Regional Blood Flow / physiology
Spectrophotometry, Ultraviolet
Terfenadine / analogs & derivatives*,  pharmacokinetics*
Verapamil / pharmacology
Reg. No./Substance:
0/Anti-Allergic Agents; 0/Calcium Channel Blockers; 0/Membrane Transport Modulators; 0/Membrane Transport Proteins; 138452-21-8/fexofenadine; 50679-08-8/Terfenadine; 52-53-9/Verapamil

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