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.

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Shen H, Yang Z, Zhao W, Zhang Y, Rodrigues AD

Drug Metab Dispos. 2013 Dec;41(12):2095-103. doi: 10.1124/dmd.113.053215. Epub 2013 Sep 11.

PubMed ID

24026623 [ View in PubMed

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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 (IC(50) of 73.4 +/- 14.8 and 8.8 +/- 1.9 microM, respectively). However, vandetanib was an even more potent inhibitor of MATE1- and MATE2K-mediated uptake of MPP(+) (IC(50) of 1.23 +/- 0.05 and 1.26 +/- 0.06 microM, respectively) and metformin (IC(50) of 0.16 +/- 0.05 and 0.30 +/- 0.09 microM, respectively). Subsequent cytotoxicity studies demonstrated that transport inhibition by vandetanib (2.5 microM) significantly decreased the sensitivity [right shift in concentration of cisplatin giving rise to 50% cell death; IC(50(CN))] of MATE1-HEK and MATE2K-HEK cells to cisplatin [IC(50(CN)) of 1.12 +/- 0.13 versus 2.39 +/- 0.44 microM; 0.85 +/- 0.09 versus 1.99 +/- 0.16 microM; P < 0.05), but not OCT2-HEK cells (1.36 +/- 0.19 versus 1.47 +/- 0.24 microM) versus vandetanib untreated cells and Mock-HEK cells [IC(50(CN)) of 2.34 +/- 0.31 microM]. 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.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Vandetanib	Solute carrier family 22 member 2	Protein	Humans	No	Inhibitor	Details

Drug Interactions

Drugs	Interaction
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