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Research ArticleArticle

Evaluation and Prediction of Potential Drug-Drug Interactions of Linagliptin Using In Vitro Cell Culture Methods

Naoki Ishiguro, Hidetada Shimizu, Wataru Kishimoto, Thomas Ebner and Olaf Schaefer
Drug Metabolism and Disposition January 2013, 41 (1) 149-158; DOI: https://doi.org/10.1124/dmd.112.048470
Naoki Ishiguro
Nippon Boehringer Ingelheim Co., Ltd., Kobe, Japan (N.I., H.S., W.K., O.S.); and Boehringer Ingelheim Pharma GmbH, Biberach, Germany (T.E.)
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Hidetada Shimizu
Nippon Boehringer Ingelheim Co., Ltd., Kobe, Japan (N.I., H.S., W.K., O.S.); and Boehringer Ingelheim Pharma GmbH, Biberach, Germany (T.E.)
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Wataru Kishimoto
Nippon Boehringer Ingelheim Co., Ltd., Kobe, Japan (N.I., H.S., W.K., O.S.); and Boehringer Ingelheim Pharma GmbH, Biberach, Germany (T.E.)
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Thomas Ebner
Nippon Boehringer Ingelheim Co., Ltd., Kobe, Japan (N.I., H.S., W.K., O.S.); and Boehringer Ingelheim Pharma GmbH, Biberach, Germany (T.E.)
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Olaf Schaefer
Nippon Boehringer Ingelheim Co., Ltd., Kobe, Japan (N.I., H.S., W.K., O.S.); and Boehringer Ingelheim Pharma GmbH, Biberach, Germany (T.E.)
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Abstract

Linagliptin is a highly potent dipeptidyl peptidase-4 (DPP-4) inhibitor approved for the treatment of type 2 diabetes. Unlike other DPP-4 inhibitors, linagliptin is cleared primarily via the bile and gut. We used a panel of stably and transiently transfected cell lines to elucidate the carrier-mediated transport processes that are involved in linagliptin disposition in vivo and to assess the potential for drug-drug interactions (DDIs). Our results demonstrate that linagliptin is a substrate of organic cation transporter 2 (OCT2) and P-glycoprotein (P-gp) but not of organic anion–transporting polypeptide 1B1 and 1B3; organic anion transporter 1, 3, and 4; OCT1; or organic cation/carnitine transporter 1 and 2, suggesting that OCT2 and P-gp play a role in the disposition of linagliptin in vivo. Linagliptin inhibits transcellular transport of digoxin by P-gp with an apparent IC50 of 66.1 μM, but it did not inhibit activity of multidrug resistance–associated protein 2 and breast cancer resistance protein as represented by transport of probe substrate into membrane vesicles from respective transporter-expressing cells. In addition, the inhibitory effect of linagliptin on major solute carrier transporter isoforms was investigated. Linagliptin showed inhibitory potency against only OCT1 and OCT2 out of all major solute carrier transporter isoforms examined, and those inhibition potencies, evaluated using three different in vitro probe substrates, were substrate-specific. Considering the low therapeutic plasma concentration of linagliptin, our data clearly suggest a very low risk for transporter-mediated DDIs with comedications in clinical practice.

Footnotes

  • This study was supported by Boehringer Ingelheim.

  • dx.doi.org/10.1124/dmd.112.048470.

  • Received August 15, 2012.
  • Accepted October 16, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (1)
Drug Metabolism and Disposition
Vol. 41, Issue 1
1 Jan 2013
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Research ArticleArticle

Potential Drug-Drug Interactions of Linagliptin

Naoki Ishiguro, Hidetada Shimizu, Wataru Kishimoto, Thomas Ebner and Olaf Schaefer
Drug Metabolism and Disposition January 1, 2013, 41 (1) 149-158; DOI: https://doi.org/10.1124/dmd.112.048470

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Research ArticleArticle

Potential Drug-Drug Interactions of Linagliptin

Naoki Ishiguro, Hidetada Shimizu, Wataru Kishimoto, Thomas Ebner and Olaf Schaefer
Drug Metabolism and Disposition January 1, 2013, 41 (1) 149-158; DOI: https://doi.org/10.1124/dmd.112.048470
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