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

0090-9556/06/3407-1182-1189$20.00
DMD 34:1182-1189, 2006

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

Niclas Petri, Ebba Bergman, Patrik Forsell, Mikael Hedeland, Ulf Bondesson, Lars Knutson, and Hans Lennernäs

Department of Pharmacy, Biopharmaceutics Research Group, Uppsala University, Uppsala, Sweden (N.P., E.B., H.L.); Department of Surgery, University Hospital, Uppsala, Sweden (P.F., L.K.); Department of Chemistry, National Veterinary Institute, Uppsala, Sweden (M.H., U.B.); and Division of Analytical Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden (U.B.)

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.

Address correspondence to: Dr. Hans Lennernäs, Professor in Biopharmaceutics, Biopharmaceutical Research Group, Department of Pharmacy, Uppsala University, Box 580, SE-751 23 Uppsala, Sweden. E-mail: hans.lennernas{at}farmaci.uu.se, http://www.farmfak.uu.se/farm/




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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.
[Abstract] [Full Text] [PDF]


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