Inhibitory Effect of Crizotinib on Creatinine Uptake by Renal Secretory Transporter OCT2

Crizotinib, a tyrosine kinase inhibitor, exhibits some cases of an increase in serum creatinine levels. Creatinine is excreted by not only glomerular filtration but also active secretion by organic cation transporters such as organic cation transporter 2 (OCT2). In the present study, we evaluated in vitro inhibitory effect of crizotinib on OCT2 by directly measuring creatinine uptake by OCT2. Coincubation of crizotinib reduced uptake of [¹⁴C]creatinine by cultured HEK293 cells expressing OCT2 (HEK293/OCT2) in a concentration-dependent manner with IC₅₀ values of 1.58 ± 0.24 μM. Preincubation or both preincubation and coincubation (preincubation/coincubation) with crizotinib showed stronger inhibitory effect on [¹⁴C]creatinine uptake compared with that in coincubation alone with IC₅₀ values of 0.499 ± 0.076 and 0.347 ± 0.040 μM, respectively. These IC₅₀ values of crizotinib on [³H]N-methyl-4-phenylpyridinium acetate uptake by OCT2 were 10-20 times higher than those of [¹⁴C]creatinine uptake. Furthermore, preincubation of crizotinib inhibited creatinine uptake by OCT2 in an apparently competitive manner. In conclusion, crizotinib at a clinically relevant concentration has the potential to inhibit creatinine transport by OCT2, suggesting an increase of serum creatinine levels in clinical use.