Abstract
The aim of this study in pigs was to investigate the local pharmacokinetics of fexofenadine in the intestine and liver by using the pig as a model for drug transport in the entero-hepatobiliary system. A parallel group design included seven pigs (10–12 weeks, 22.2–29.5 kg) in three groups (G1, G2, G3), and a jejunal single-pass perfusion combined with sampling from the bile duct and the portal, hepatic, and superior caval veins was performed. Fexofenadine was perfused through the jejunal segment alone (G1: 120 mg/l, total dose 24 mg) or with two different verapamil doses (G2: 175 mg/l, total dose 35 mg; and G3: 1000 mg/l, total dose 200 mg). The animals were fully anesthetized and monitored throughout the experiment. Fexofenadine had a low liver extraction (EH; mean ± S.E.M.), and the given doses of verapamil did not affect the EH (0.13 ± 0.04, 0.16 ± 0.03, and 0.12 ± 0.02 for G1, G2, and G3, respectively) or biliary clearance. The EH for verapamil and antipyrine agreed well with human in vivo data. Verapamil did not increase the intestinal absorption of fexofenadine, even though the jejunal permeability of fexofenadine, verapamil, and antipyrine showed a tendency to increase in G2. This combined perfusion and hepatobiliary sampling method showed that verapamil did not affect the transport of fexofenadine in the intestine or liver. In this model the EH values for both verapamil and antipyrine were similar to the corresponding values in vivo in humans.
Footnotes
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This work was supported by the Swedish Foundation for Strategic Research.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.105.008409.
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ABBREVIATIONS: ABCB1, ATP-binding cassette B1; OATP, organic anion-transporting polypeptide; G1, group 1; G2, group 2; G3, group 3; PEG, polyethylene glycol; V.P., portal vein; V.H., hepatic vein; V., superior caval vein; HPLC, high-performance liquid chromatography; AUC, area under the concentration-time curve; Peff, jejunal effective permeability; fabs, fraction of the dose available that is absorbed; Ae, bile, amount of dose excreted in the bile; fe, bile, fraction of dose excreted in the bile; Iin, max, maximum concentration entering the liver; CLbile, biliary clearance.
- Received November 16, 2005.
- Accepted April 11, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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