Organic anion transporter oatp2-mediated interaction between digoxin and amiodarone in the rat liver

• Published in: Pharmaceutical research Vol. 19; no. 6; pp. 738 - 743
• Main Authors: KODAWARA, Takaaki, MASUDA, Satohiro, WAKASUGI, Hiroko, UWAI, Yuichi, FUTAMI, Takahiro, SAITO, Hideyuki, ABE, Takaaki, INUI, Ken-Ichi
• Format: Journal Article
• Language: English
• Published: New York, NY Springer 01.06.2002; Springer Nature B.V
• Subjects: Amiodarone - metabolism; Animals; Antiarythmic agents; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; Biological and medical sciences; Cardiotonic agents; Cardiovascular system; Cells, Cultured; Digoxin - metabolism; Dose-Response Relationship, Drug; Drug Interactions - physiology; Female; Hepatocytes - cytology; Hepatocytes - drug effects; Hepatocytes - metabolism; Humans; Liver - cytology; Liver - drug effects; Liver - metabolism; Male; Medical sciences; Organic Anion Transporters; Organic Cation Transport Proteins - metabolism; Pharmacology. Drug treatments; Rats; Rats, Wistar; Xenopus; Antianginal agent; Drug combination; Cardiotonic agent; Digoxin; Rat; Digestive system; Liver; Biological transport; Rodentia; P Glycoprotein; Amiodarone; Antiarrhythmic agent; In vitro; Iodine Organic compounds; Conveyor; Vertebrata; Organic anion; Mammalia; Animal; Glycoside; Drug interaction; Mechanism of action; Digitalis drug
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1023/A:1016184211491

The interaction between amiodarone and digoxin has been known to increase serum concentrations of digoxin in humans and rats. In this study, we assessed the molecular mechanism(s) of that drug interaction, focusing on digoxin transport mediated by P-glycoprotein (Pgp) and by rat liver organic anion transporter (oatp2). Digoxin transport by Pgp and oatp2 was assessed using Pgp-overexpressing transfectant LLC-GA5-COL150 monolayers and oatp2-expressing Xenopus oocytes, respectively. The digoxin uptake into the isolated rat hepatocytes was also examined. Amiodarone (10 microM) inhibited slightly the transcellular transport of digoxin in LLC-GA5-COL150 monolayers, whereas itraconazole (10 microM), a potent Pgp inhibitor, markedly blocked the transport. The digoxin uptake by the isolated rat hepatocytes and by the oatp2-expressing Xenopus oocytes was decreased markedly in the presence of amiodarone but not in the presence of itraconazole. In addition, amiodarone inhibited the oatp2-mediated digoxin uptake in a competitive manner with an apparent inhibition constant value of 1.8 microM. These findings suggest that rat oatp2 rather than Pgp may be one of the interaction sites for digoxin and amiodarone in the liver.