title: Pharmacokinetic variability of flecainide in younger Japanese patients and mechanisms for renal excretion and intestinal absorption.
abstract: The aims of the present study were to evaluate the variability of pharmacokinetics of flecainide in young Japanese patients and to investigate the mechanisms of renal excretion and intestinal absorption of the drug using cultured epithelial cells. First the plasma concentration data of flecainide was analysed in 16 Japanese patients aged between 0.07 and 18.30 years using a one-compartment model. Considerable interindividual variability was observed in the oral clearance (CL/F) and the apparent volume of distribution (V/F) of flecainide in the young patients. Flecainide was transported selectively in the basolateral-to-apical direction in P-glycoprotein-expressing renal epithelial LLC-GA5-COL150 cell monolayers. The uptake of flecainide into intestinal epithelial LS180 cells was decreased significantly by acidification of the extracellular medium, and was inhibited by tertiary amines, such as diphenhydramine and quinidine. These findings in the present study suggest that flecainide is excreted by P-glycoprotein in the renal tubule and is taken up by the postulated H(+)/tertiary amine antiporter in the intestine, and that functional variability of not only the hepatic drug-metabolizing enzymes, but also the transporters in the kidney and intestine, may be responsible for the interindividual variability of systemic clearance (CL) and/or the bioavailability (F) of flecainide.
authors.affiliation: Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
authors.forename: Asuka
authors.initials: A
authors.lastname: Horie
authors.forename: Kazuya
authors.initials: K
authors.lastname: Ishida
authors.forename: Kaito
authors.initials: K
authors.lastname: Shibata
authors.forename: Masato
authors.initials: M
authors.lastname: Taguchi
authors.forename: Ayaka
authors.initials: A
authors.lastname: Ozawa
authors.forename: Keiichi
authors.initials: K
authors.lastname: Hirono
authors.forename: Fukiko
authors.initials: F
authors.lastname: Ichida
authors.forename: Yukiya
authors.initials: Y
authors.lastname: Hashimoto
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000284:Administration, Oral; D000293:Adolescent; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics*; D044466:Asian People; D001682:Biological Availability; D001692:Biological Transport; D002478:Cells, Cultured; D002648:Child; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D005424:Flecainide / Q000493:pharmacokinetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007408:Intestinal Absorption; D008297:Male; D008954:Models, Biological; D013552:Swine; D014018:Tissue Distribution
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000889:Anti-Arrhythmia Agents; D005424:Flecainide
keywords: P-glycoprotein; flecainide; intestinal absorption; pharmacokinetics; renal tubular secretion