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

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

Author information

1
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.
2
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.

Abstract

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

PMID:
28336299
DOI:
10.1016/j.xphs.2017.03.013
[Indexed for MEDLINE]

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