Role of organic anion transporting polypeptide 2 in pharmacokinetics of digoxin and beta-methyldigoxin in rats.
Recently, we found that potent P-glycoprotein (P-gp) inhibitors, such as verapamil and cyclosporin A, markedly modulated the pharmacokinetics of digoxin in rats, whereas they did not affect beta-methyldigoxin pharmacokinetics significantly. Digoxin is also a substrate of rat organic anion transporting polypeptide 2 (Oatp2). Here, we compared the magnitude of Oatp2-mediated drug interaction of digoxin and beta-methyldigoxin using amiodarone as an Oatp2 inhibitor in rats. Amiodarone (20 mg/kg) given intravenously significantly increased plasma levels and decreased biliary excretion, liver distribution, and intestinal distribution of digoxin administered intravenously at a dose of 10 mug/kg. Amiodarone also significantly decreased biliary excretion and liver distribution of beta-methyldigoxin, but the change in plasma levels of beta-methyldigoxin was quite small. These findings may give a clue in selecting these cardiac glycosides in clinical pharmacotherapy for patients receiving multiple drugs towards escape from Oatp2-mediated drug interactions.
Funakoshi
Sachiyo
S
Department of Pharmaceutics and Therapeutics, Programs for Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
Murakami
Teruo
T
Yumoto
Ryoko
R
Kiribayashi
Yoshie
Y
Takano
Mikihisa
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology; D000638:Amiodarone / Q000494:pharmacology; D000818:Animals; D004077:Digoxin / Q000493:pharmacokinetics*; D004347:Drug Interactions; D008297:Male; D008520:Medigoxin / Q000493:pharmacokinetics*; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar
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; D008520:Medigoxin; D000638:Amiodarone