Abstract
Cimetidine, an H2 receptor antagonist, has been used to investigate the tubular secretion of organic cations in human kidney. We report a systematic comprehensive analysis of the inhibition potency of cimetidine for the influx and efflux transporters of organic cations [human organic cation transporter 1 (hOCT1) and hOCT2 and human multidrug and toxin extrusion 1 (hMATE1) and hMATE2-K, respectively]. Inhibition constants (Ki) of cimetidine were determined by using five substrates [tetraethylammonium (TEA), metformin, 1-methyl-4-phenylpyridinium, 4-(4-(dimethylamino)styryl)-N-methylpyridinium, and m-iodobenzylguanidine]. They were 95 to 146 μM for hOCT2, providing at most 10% inhibition based on its clinically reported plasma unbound concentrations (3.6–7.8 μM). In contrast, cimetidine is a potent inhibitor of MATE1 and MATE2-K with Ki values (μM) of 1.1 to 3.8 and 2.1 to 6.9, respectively. The same tendency was observed for mouse Oct1 (mOct1), mOct2, and mouse Mate1. Cimetidine showed a negligible effect on the uptake of metformin by mouse kidney slices at 20 μM. Cimetidine was administered to mice by a constant infusion to achieve a plasma unbound concentration of 21.6 μM to examine its effect on the renal disposition of Mate1 probes (metformin, TEA, and cephalexin) in vivo. The kidney- and liver-to-plasma ratios of metformin both were increased 2.4-fold by cimetidine, whereas the renal clearance was not changed. Cimetidine also increased the kidney-to-plasma ratio of TEA and cephalexin 8.0- and 3.3-fold compared with a control and decreased the renal clearance from 49 to 23 and 11 to 6.6 ml/min/kg, respectively. These results suggest that the inhibition of MATEs, but not OCT2, is a likely mechanism underlying the drug-drug interactions with cimetidine in renal elimination.
Footnotes
This study was supported in part by the Japan Society for the Promotion of Science [Grant-in-Aid for Scientific Research (A) 20249008 (to Y.S.) and Grant-in-Aid for Scientific Research (B) 23390034 (to H.K.)]; and Health and Labor Sciences Research Grants (Research on Regulatory Science of Pharmaceuticals and Medical Devices) (to Y.S.).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- OCT
- organic cation transporter
- hOCT
- human OCT
- mOct
- mouse OCT
- ASP
- 4-(4-(dimethylamino)styryl)-N-methylpyridinium
- DDI
- drug-drug interaction
- LC-MS/MS
- liquid chromatography-tandem mass spectrometry
- MATE
- multidrug and toxin extrusion
- hMATE
- human MATE
- mMate
- mouse MATE
- MIBG
- m-iodobenzylguanidine
- MPP+
- 1-methyl-4-phenylpyridinium
- TEA
- tetraethylammonium
- HEK
- human embryonic kidney
- CL
- clearance.
- Received June 11, 2011.
- Accepted November 8, 2011.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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