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 IC50values 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 IC50values of 0.499 ± 0.076 and 0.347 ± 0.040 μM, respectively. These IC50values 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.
Department of Membrane Transport of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
Hiroshi
H
Arakawa
Department of Membrane Transport of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
Saki
S
Omote
Department of Membrane Transport of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan. Electronic address: tamai@p.kanazawa-u.ac.jp.
Ikumi
I
Tamai
D001692:Biological Transport / Q000187:drug effects; D003404:Creatinine / Q000378:metabolism*; D000077547:Crizotinib; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D000075102:Organic Cation Transporter 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*
D000075102:Organic Cation Transporter 2; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; C491013:SLC22A2 protein, human; D000077547:Crizotinib; D003404:Creatinine
OCT2; creatinine; crizotinib; kidney; secretion; transporter