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Research ArticleMetabolism, Transport, and Pharmacogenomics

Competitive Inhibition of the Luminal Efflux by Multidrug and Toxin Extrusions, but Not Basolateral Uptake by Organic Cation Transporter 2, Is the Likely Mechanism Underlying the Pharmacokinetic Drug-Drug Interactions Caused by Cimetidine in the Kidney

Sumito Ito, Hiroyuki Kusuhara, Miyu Yokochi, Junko Toyoshima, Katsuhisa Inoue, Hiroaki Yuasa and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics February 2012, 340 (2) 393-403; DOI: https://doi.org/10.1124/jpet.111.184986
Sumito Ito
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Hiroyuki Kusuhara
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Miyu Yokochi
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Junko Toyoshima
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Katsuhisa Inoue
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Hiroaki Yuasa
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Yuichi Sugiyama
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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.

    http://dx.doi.org/10.1124/jpet.111.184986.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • 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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Journal of Pharmacology and Experimental Therapeutics: 340 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 340, Issue 2
1 Feb 2012
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Competitive Inhibition of the Luminal Efflux by Multidrug and Toxin Extrusions, but Not Basolateral Uptake by Organic Cation Transporter 2, Is the Likely Mechanism Underlying the Pharmacokinetic Drug-Drug Interactions Caused by Cimetidine in the Kidney
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Research ArticleMetabolism, Transport, and Pharmacogenomics

Cimetidine as In Vivo Inhibitor of MATEs, but Not OCT2

Sumito Ito, Hiroyuki Kusuhara, Miyu Yokochi, Junko Toyoshima, Katsuhisa Inoue, Hiroaki Yuasa and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics February 1, 2012, 340 (2) 393-403; DOI: https://doi.org/10.1124/jpet.111.184986

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Research ArticleMetabolism, Transport, and Pharmacogenomics

Cimetidine as In Vivo Inhibitor of MATEs, but Not OCT2

Sumito Ito, Hiroyuki Kusuhara, Miyu Yokochi, Junko Toyoshima, Katsuhisa Inoue, Hiroaki Yuasa and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics February 1, 2012, 340 (2) 393-403; DOI: https://doi.org/10.1124/jpet.111.184986
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