Dmd053215 2095..2103

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 6 14.8 and 8.8 6 1.9 mM, respectively). However, vandetanib was an even more potent inhibitor of MATE1and MATE2K-mediated uptake of MPP (IC50 of 1.236 0.05 and 1.266 0.06 mM, respectively) and metformin (IC50 of 0.16 6 0.05 and 0.30 6 0.09 mM, respectively). Subsequent cytotoxicity studies demonstrated that transport inhibition by vandetanib (2.5 mM) 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 6 0.13 versus 2.39 6 0.44 mM; 0.85 6 0.09 versus 1.99 6 0.16 mM; P < 0.05), but not OCT2-HEK cells (1.36 6 0.19 versus 1.47 6 0.24 mM) versus vandetanib untreated cells and Mock-HEK cells [IC50(CN) of 2.34 6 0.31 mM]. 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.