title: MDR1-mediated interaction of digoxin with antiarrhythmic or antianginal drugs.
abstract: The multidrug transporter, MDR1-mediated interaction of digoxin with antiarrhythmic or antianginal drugs was examined in vitro by using the MDR1-overexpressing LLC-GA5-COL150 cells, which were established by transfection with human MDR1 cDNA into porcine kidney epithelial LLC-PK(1) cells. Amiodarone, its active metabolite monodesethyl-amiodarone (DEA), and quinidine markedly inhibited the basal-to-apical transport (renal secretion) of [(3)H]digoxin and increased the apical-to-basal transport (reabsorption), but cibenzoline and lidocaine showed slight inhibition of the transport, and disopyramide and mexiletin had no such effects. The IC(50) values for amiodarone, DEA and quinidine on [(3)H]digoxin transport in LLC-GA5-COL150 cells were 5.48 microM, 1.27 microM and 9.52 microM, respectively. These were comparable to, or only several times the achievable concentration in clinical use, suggesting that MDR1 could be responsible for the drug interaction between digoxin and amiodarone found in clinical reports and that DEA contributes the elevation of digoxin serum concentration. Similarly, dipyridamole altered the transport, but isosorbide showed only slight modification of the transport. The IC(50) value for dipyridamole was 40.0 microM, also only several times the achievable concentration in clinical use, indicating a risk of interaction.
authors.affiliation: Department of Hospital Pharmacy, School of Medicine, Kobe University, Japan.
authors.forename: Mikio
authors.initials: M
authors.lastname: Kakumoto
authors.forename: Kohji
authors.initials: K
authors.lastname: Takara
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakaeda
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Tanigawara
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kita
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Okumura
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000638:Amiodarone / Q000493:pharmacokinetics; D000787:Angina Pectoris / Q000188:drug therapy*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics*; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D004077:Digoxin / Q000493:pharmacokinetics*; D004347:Drug Interactions / Q000502:physiology; D006801:Humans; D018374:LLC-PK1 Cells; D011802:Quinidine / Q000493:pharmacokinetics; D013552:Swine
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000889:Anti-Arrhythmia Agents; D004077:Digoxin; D011802:Quinidine; D000638:Amiodarone