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  • Effects of verapamil on the pharmacokinetics and hepatobiliary disposition of fexofenadine in pigs.

Effects of verapamil on the pharmacokinetics and hepatobiliary disposition of fexofenadine in pigs.

European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences (2013-10-01)
Erik Sjögren, Mikael Hedeland, Ulf Bondesson, Hans Lennernäs
ABSTRACT

The pharmacokinetics (PK) of fexofenadine (FEX) in pigs were investigated with the focus on exploring the interplay between hepatic transport and metabolism when administered intravenously (iv) alone or with verapamil. The in vivo pig model enabled simultaneous sampling from plasma (pre-liver, post-liver and peripheral), bile and urine. Each animal was administered FEX 35mg iv alone or with verapamil 35mg. Plasma, bile and urine were analyzed with liquid chromatography-tandem mass spectrometry. Non-compartmental analysis (NCA) was used to estimate traditional PK parameters. In addition, a physiologically based pharmacokinetic (PBPK) model consisting of 11 compartments (6 tissues +5 sample sites) was applied for mechanistic elucidation and estimation of individual PK parameters. FEX had a terminal half-life of 1.7h and a liver extraction of 3%. The fraction of the administered dose of unchanged FEX excreted into the bile was 25% and the bile exposure was more than 100 times higher than the portal vein total plasma exposure, indicating carrier-mediated (CM) disposition processes in the liver. 23% of the administered dose of FEX was excreted unchanged in the urine. An increase in FEX plasma exposure (+50%) and a decrease in renal clearance (-61%) were detected by NCA as a direct effect of concomitant administration of verapamil. However, analysis of the PBPK model also revealed that biliary clearance was significantly inhibited (-53%) by verapamil. In addition, PBPK analysis established that metabolism and CM uptake were important factors in the disposition of FEX in the liver. In conclusion, this study demonstrated that CM transport of FEX in both liver and kidneys was inhibited by a single dose of verapamil.

MATERIALS
Product Number
Brand
Product Description

Pancuronium bromide, European Pharmacopoeia (EP) Reference Standard
Pancuronium bromide for system suitability, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Xylazine, ≥99%
Sigma-Aldrich
Pancuronium bromide
Atropine, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Fexofenadine hydrochloride, >98% (HPLC)
Sigma-Aldrich
β-D-Allose, rare aldohexose sugar
Atropine for peak identification, European Pharmacopoeia (EP) Reference Standard
USP
Fexofenadine hydrochloride, United States Pharmacopeia (USP) Reference Standard
Fexofenadine hydrochloride, European Pharmacopoeia (EP) Reference Standard