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


METHODS
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.


RESULTS
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.


CONCLUSIONS
These findings suggest that rat oatp2 rather than Pgp may be one of the interaction sites for digoxin and amiodarone in the liver.
Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine Kyoto University, Japan.
Takaaki
T
Kodawara
Satohiro
S
Masuda
Hiroko
H
Wakasugi
Yuichi
Y
Uwai
Takahiro
T
Futami
Hideyuki
H
Saito
Takaaki
T
Abe
Ken-ichi
K
Inu
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000638:Amiodarone / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004077:Digoxin / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D005260:Female; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014981:Xenopus
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; C503597:Slco1a4 protein, rat; C451262:Slco1c1 protein, rat; D004077:Digoxin; D000638:Amiodarone