title: Efflux transport of N-monodesethylamiodarone by the human intestinal cell-line Caco-2 cells.
abstract: Amiodarone (AMD) is a benzofurane derivative with class III antiarrhythmic activity that is effective in controlling intractable cardiac arrhythmias. One of the most common and serious drug interactions in clinical practice is the interaction between digoxin and an antiarrhythmic agent. It has been reported that AMD and N-monodesethylamiodarone (DEA), the active metabolite of AMD, inhibit the P-glycoprotein (P-gp/MDR1)-mediated digoxin transport. However, the intestinal transport processes of AMD and DEA have not been fully revealed. In this study, we focused on the intestinal transport mechanism of DEA and characterized the intestinal transport of DEA using Caco-2 cells. Basal-to-apical transport of DEA by Caco-2 cells was greater than apical-to-basal transport. The relationship between concentration and basal-to-apical flux rate appeared to approach saturation. The uptake of DEA by Caco-2 cells was increased in the presence of typical ATP-depletion compounds and thyroid hormones. On the other hand, substrates for P-gp, multidrug resistance-associated proteins (MRPs/ABCCs) and breast cancer resistance protein (BCRP/ABCG2) had no effect on the efflux of DEA. These results suggest that an ATP-binding cassette (ABC) transporter, which is different from P-gp, MRPs and BCRP, mediates the efflux of DEA across the apical membrane in Caco-2 cells and that thyroid hormone inhibits this transporter.
authors.affiliation: Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, and Department of Pharmacy, Sapporo City General Hospital, Japan.
authors.forename: Emi
authors.initials: E
authors.lastname: Kimoto
authors.forename: Satoru
authors.initials: S
authors.lastname: Seki
authors.forename: Shirou
authors.initials: S
authors.lastname: Itagaki
authors.forename: Maya
authors.initials: M
authors.lastname: Matsuura
authors.forename: Masaki
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hirano
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Goto
authors.forename: Koji
authors.initials: K
authors.lastname: Tadano
authors.forename: Ken
authors.initials: K
authors.lastname: Iseki
mesh_terms: D000255:Adenosine Triphosphate / Q000502:physiology; D000638:Amiodarone / Q000031:analogs & derivatives* / Q000378:metabolism; D001693:Biological Transport, Active; D018938:Caco-2 Cells; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004347:Drug Interactions; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000166:cytology; D013056:Spectrophotometry, Ultraviolet; D013963:Thyroid Hormones / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology