Effects of verapamil on the pharmacokinetics and hepatobiliary disposition of fexofenadine in pigs.
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.
Department of Pharmacy, Biopharmaceutic Research Group, Uppsala University, Box 580, SE-751 23 Uppsala, Sweden. Electronic address: erik.sjogren@farmaci.uu.se.
Erik
E
Sjögren
Department of Medicinal Chemistry, Division of Analytical Pharmaceutical Chemistry, Uppsala University, Box 573, SE-751 23 Uppsala, Sweden; National Veterinary Institute (SVA), Department of Chemistry, Environment and Feed Hygiene, SE-751 89 Uppsala, Sweden.
Mikael
M
Hedeland
Department of Medicinal Chemistry, Division of Analytical Pharmaceutical Chemistry, Uppsala University, Box 573, SE-751 23 Uppsala, Sweden; National Veterinary Institute (SVA), Department of Chemistry, Environment and Feed Hygiene, SE-751 89 Uppsala, Sweden.
Ulf
U
Bondesson
Department of Pharmacy, Biopharmaceutic Research Group, Uppsala University, Box 580, SE-751 23 Uppsala, Sweden.
Hans
H
Lennernäs
D000818:Animals; D001646:Bile / Q000187:drug effects* / Q000378:metabolism; D001692:Biological Transport; D001711:Biotransformation; D002853:Chromatography, Liquid; D004347:Drug Interactions; D065669:Hepatobiliary Elimination / Q000187:drug effects*; D007262:Infusions, Intravenous; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D013552:Swine; D053719:Tandem Mass Spectrometry; D016593:Terfenadine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D014700:Verapamil / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D016593:Terfenadine; D014700:Verapamil; C093230:fexofenadine
Carrier-mediated transport; Drug interaction; Fexofenadine; Hepatic disposition; Physiologically based pharmacokinetic modeling