title: Rapid stimulating effect of the antiarrhythmic agent amiodarone on absorption of organic anion compounds.
abstract: In a clinical setting, changes in pharmacokinetics due to drug-drug interactions can often directly affect the therapeutic safety and efficacy of drugs. Recently, interest has been shown in drug-drug interactions in the intestine. It is now recognized that changes in the functions of drug transporters substantially influence the absorption of administered drugs from the intestine. Amiodarone (AMD) is a potent drug used in the treatment of serious supraventricular and ventricular tachyarrhythmias. Despite its potent pharmacological effects, its wide clinical use is precluded by drug-drug interactions. In this study, we characterized the transporter function between AMD and various compounds in human intestinal model Caco-2 cells. AMD significantly and rapidly increased the uptake of [(3)H]estrone-3-sulfate (E-3-S) for 5 min. The apical-to-basal transport of [(3)H]E-3-S was significantly increased by AMD. The AMD-stimulated [(3)H]E-3-S uptake was inhibited by organic anion transporting polypeptide (OATP) substrates. Caco-2 cells treated with AMD showed increased OATP2B1 expression on the cell surface. AMD also increased the absorption of sulfobromophthalein (BSP), which is a typical organic anion compound, and the expression level of Oatp2b1 at the membrane in in vivo experiments. The results indicate that AMD induces OATP2B1/Oatp2b1 expression at the membrane in the intestine and enhances absorption of organic anion compounds.
authors.affiliation: Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Segawa
authors.forename: Jiro
authors.initials: J
authors.lastname: Ogura
authors.forename: Satoru
authors.initials: S
authors.lastname: Seki
authors.forename: Shirou
authors.initials: S
authors.lastname: Itagaki
authors.forename: Natsuko
authors.initials: N
authors.lastname: Takahashi
authors.forename: Masaki
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hirano
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Ken
authors.initials: K
authors.lastname: Iseki
mesh_terms: D000638:Amiodarone / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D018938:Caco-2 Cells; D004347:Drug Interactions; D004970:Estrone / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D050556:Fatty Acid-Binding Proteins / Q000187:drug effects*; D005768:Gastrointestinal Hormones; D006801:Humans; D008871:Microvilli / Q000378:metabolism; D027361:Organic Anion Transporters / Q000096:biosynthesis; D051381:Rats; D013448:Sulfobromophthalein / Q000493:pharmacokinetics
chemical_list: D000889:Anti-Arrhythmia Agents; D050556:Fatty Acid-Binding Proteins; D005768:Gastrointestinal Hormones; D027361:Organic Anion Transporters; C450859:SLCO2B1 protein, human; D013448:Sulfobromophthalein; C057275:fatty acid-binding protein 6; D004970:Estrone; D000638:Amiodarone; C017296:estrone sulfate