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

J Pharm Sci. 2017 Sep;106(9):2899-2903. doi: 10.1016/j.xphs.2017.03.013. Epub 2017 Mar 21.


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.

Keywords: OCT2; creatinine; crizotinib; kidney; secretion; transporter.

MeSH terms

  • Biological Transport / drug effects
  • Creatinine / metabolism*
  • Crizotinib
  • HEK293 Cells
  • Humans
  • Kidney / drug effects
  • Kidney / metabolism
  • Kinetics
  • Organic Cation Transporter 2 / antagonists & inhibitors*
  • Organic Cation Transporter 2 / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrazoles / pharmacology*
  • Pyridines / pharmacology*


  • Organic Cation Transporter 2
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyridines
  • SLC22A2 protein, human
  • Crizotinib
  • Creatinine