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Drug Metabolism and Disposition Fast Forward
First published on April 18, 2006; DOI: 10.1124/dmd.105.008409

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Received for publication November 17, 2005.
Revised April 10, 2006.
Accepted for publication April 11, 2006.

FIRST-PASS EFFECTS OF VERAPAMIL ON THE INTESTINAL ABSORPTION AND LIVER DISPOSITION OF FEXOFENADINE IN THE PORCINE MODEL

Niclas Petri 1, Ebba Bergman 1, Patrik Forsell 1, Mikael Hedeland 2, Ulf Bondesson 2, Lars Knutson 1, Hans Lennernas 1*

1 Uppsala University 2 National Veterinary Institute

* Address correspondence to: E-mail: hans.lennernas{at}farmaci.uu.se

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 model for drug transport in the entero-hepatobiliary system. A parallel group design including seven pigs (10-12 weeks, 22.2-29.5 kg) in three groups (G1, G2, G3) using 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 anaesthetized and monitored throughout the experiment. Fexofenadine had a low liver extraction (EH; mean ± SEM) and neither the given doses of verapamil did 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. The model had a similar EH for both verapamil and antipyrine as the corresponding values in vivo in humans


Key words: ABC transporters, biliary excretion, drug absorption, hepatic transport, hepatobiliary transport, intestinal transport, membrane-protein interactions, oral absorption


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E. Sjodin, H. Fritsch, U. G. Eriksson, U. Logren, A. Nordgren, P. Forsell, L. Knutson, and H. Lennernas
Intestinal and Hepatobiliary Transport of Ximelagatran and Its Metabolites in Pigs
Drug Metab. Dispos., August 1, 2008; 36(8): 1519 - 1528.
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