Inhibitory effects of vandetanib on creatinine transport via renal organic cation transporter OCT2.

Vandetanib (ZD6474, Zactima®, Caprelsa®) is a newly developed dual tyrosine kinase inhibitor of vascular endothelial growth factor and epidermal growth factor receptor. Recently, several reports have indicated the interaction of vandetanib with tyrosine kinase inhibitors and transporters. However, these characteristics of vandetanib remain unclear. We examined the interaction of vandetanib with the human organic cation transporter 2 (hOCT2) stably expressed in human embryonic kidney (HEK) 293 cells. The specific uptake of vandetanib was not observed in hOCT2-expressing HEK293 cells. Vandetanib inhibited the uptake of creatinine mediated by hOCT2 in a dose-dependent manner. The IC value for vandetanib inhibition of creatinine uptake by hOCT2 was 3.7 ± 1.0 μM (average ± SE of three separate experiments). The IC value of cimetidine and trimethoprim for hOCT2 were 100 ± 13.5 and 52.1 ± 8.0 μM, respectively. Vandetanib showed markedly higher affinity for hOCT2 than cimetidine and trimethoprim. These results suggest that hOCT2 may play a crucial role in elevating the serum creatinine levels, as well as increasing the risk of renal impairment during vandetanib administration.