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Organic Anion Transporter oatp2-Mediated Interaction between Digoxin and Amiodarone in the Rat Liver

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Abstract

Purpose. 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 μM) inhibited slightly the transcellular transport of digoxin in LLC-GA5-COL150 monolayers, whereas itraconazole (10 μM), 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 μM.

Conclusion. These findings suggest that rat oatp2 rather than Pgp may be one of the interaction sites for digoxin and amiodarone in the liver.

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Authors and Affiliations

  1. Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine Kyoto University, Sakyo-ku, Kyoto, 606-8507, Japan

    Takaaki Kodawara, Satohiro Masuda, Hiroko Wakasugi, Yuichi Uwai, Takahiro Futami, Hideyuki Saito & Ken-ichi Inui

  2. Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, 980-8574, Japan

    Takaaki Abe

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  1. Takaaki Kodawara
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  2. Satohiro Masuda
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  4. Yuichi Uwai
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  7. Takaaki Abe
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  8. Ken-ichi Inui
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Correspondence to Ken-ichi Inui.

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Kodawara, T., Masuda, S., Wakasugi, H. et al. Organic Anion Transporter oatp2-Mediated Interaction between Digoxin and Amiodarone in the Rat Liver. Pharm Res 19, 738–743 (2002). https://doi.org/10.1023/A:1016184211491

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