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Research ArticleArticle

Assessment of Vandetanib as an Inhibitor of Various Human Renal Transporters: Inhibition of Multidrug and Toxin Extrusion as a Possible Mechanism Leading to Decreased Cisplatin and Creatinine Clearance

Hong Shen, Zheng Yang, Weiping Zhao, Yueping Zhang and A. David Rodrigues
Drug Metabolism and Disposition December 2013, 41 (12) 2095-2103; DOI: https://doi.org/10.1124/dmd.113.053215
Hong Shen
Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, Princeton, New Jersey
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Zheng Yang
Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, Princeton, New Jersey
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Weiping Zhao
Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, Princeton, New Jersey
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Yueping Zhang
Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, Princeton, New Jersey
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A. David Rodrigues
Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, Princeton, New Jersey
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Abstract

Vandetanib was evaluated as an inhibitor of human organic anion transporter 1 (OAT1), OAT3, organic cation transporter 2 (OCT2), and multidrug and toxin extrusion (MATE1 and MATE2K) transfected (individually) into human embryonic kidney 293 cells (HEK293). Although no inhibition of OAT1 and OAT3 was observed, inhibition of OCT2-mediated uptake of 1-methyl-4-phenylpyridinium (MPP+) and metformin was evident (IC50 of 73.4 ± 14.8 and 8.8 ± 1.9 µM, respectively). However, vandetanib was an even more potent inhibitor of MATE1- and MATE2K-mediated uptake of MPP+ (IC50 of 1.23 ± 0.05 and 1.26 ± 0.06 µM, respectively) and metformin (IC50 of 0.16 ± 0.05 and 0.30 ± 0.09 µM, respectively). Subsequent cytotoxicity studies demonstrated that transport inhibition by vandetanib (2.5 µM) significantly decreased the sensitivity [right shift in concentration of cisplatin giving rise to 50% cell death; IC50(CN)] of MATE1-HEK and MATE2K-HEK cells to cisplatin [IC50(CN) of 1.12 ± 0.13 versus 2.39 ± 0.44 µM; 0.85 ± 0.09 versus 1.99 ± 0.16 µM; P < 0.05), but not OCT2-HEK cells (1.36 ± 0.19 versus 1.47 ± 0.24 µM) versus vandetanib untreated cells and Mock-HEK cells [IC50(CN) of 2.34 ± 0.31 µM]. In summary, the results show that vandetanib is a potent inhibitor of MATE1 and MATE2K (versus OCT2). Inhibition of the two transporters may explain why there are reports of decreased creatinine clearance, and increased cisplatin nephrotoxicity (reduced cisplatin clearance), in some subjects receiving vandetanib therapy.

Footnotes

    • Received June 6, 2013.
    • Accepted September 11, 2013.
  • This study is supported by Bristol-Myers Squibb Company.

  • dx.doi.org/10.1124/dmd.113.053215.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (12)
Drug Metabolism and Disposition
Vol. 41, Issue 12
1 Dec 2013
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Research ArticleArticle

Inhibition of MATE1 and MATE2K by Vandetanib

Hong Shen, Zheng Yang, Weiping Zhao, Yueping Zhang and A. David Rodrigues
Drug Metabolism and Disposition December 1, 2013, 41 (12) 2095-2103; DOI: https://doi.org/10.1124/dmd.113.053215

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Research ArticleArticle

Inhibition of MATE1 and MATE2K by Vandetanib

Hong Shen, Zheng Yang, Weiping Zhao, Yueping Zhang and A. David Rodrigues
Drug Metabolism and Disposition December 1, 2013, 41 (12) 2095-2103; DOI: https://doi.org/10.1124/dmd.113.053215
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