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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Interactions of Human Organic Anion Transporters with Diuretics

Habib Hasannejad, Michio Takeda, Kentarou Taki, Ho Jung Shin, Ellappan Babu, Promsuk Jutabha, Suparat Khamdang, Mahmoud Aleboyeh, Maristela Lika Onozato, Akihiro Tojo, Atsushi Enomoto, Naohiko Anzai, Shinichi Narikawa, Xiu-Lin Huang, Toshimitsu Niwa and Hitoshi Endou
Journal of Pharmacology and Experimental Therapeutics March 2004, 308 (3) 1021-1029; DOI: https://doi.org/10.1124/jpet.103.059139
Habib Hasannejad
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Michio Takeda
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Kentarou Taki
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Ho Jung Shin
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Ellappan Babu
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Promsuk Jutabha
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Suparat Khamdang
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Mahmoud Aleboyeh
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Maristela Lika Onozato
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Akihiro Tojo
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Atsushi Enomoto
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Naohiko Anzai
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Shinichi Narikawa
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Xiu-Lin Huang
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Toshimitsu Niwa
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Hitoshi Endou
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Abstract

The tubular secretion of diuretics in the proximal tubule has been shown to be critical for the action of drugs. To elucidate the molecular mechanisms for the tubular excretion of diuretics, we have elucidated the interactions of human organic anion transporters (hOATs) with diuretics using cells stably expressing hOATs. Diuretics tested were thiazides, including chlorothiazide, cyclothiazide, hydrochlorothiazide, and trichlormethiazide; loop diuretics, including bumetanide, ethacrynic acid, and furosemide; and carbonic anhydrase inhibitors, including acetazolamide and methazolamide. These diuretics inhibited organic anion uptake mediated by hOAT1, hOAT2, hOAT3, and hOAT4 in a competitive manner. hOAT1 exhibited the highest affinity interactions for thiazides, whereas hOAT3 did those for loop diuretics. hOAT1, hOAT3, and hOAT4 but not hOAT2, mediated the uptake of bumetanide. hOAT3 and hOAT4, but not hOAT1 mediated the efflux of bumetanide. hOAT1 and hOAT3, but not hOAT2 and hOAT4 mediated the uptake of furosemide. In conclusion, it was suggested that hOAT1 may play an important role in the basolateral uptake of thiazides, and hOAT3 in the uptake of loop diuretics. In addition, it was also suggested that bumetanide taken up by hOAT3 and/or hOAT1 is excreted into the urine by hOAT4.

Footnotes

  • This study was supported in part by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology (nos. 11671048, 11694310, 13671128, and 15590858) and the Science Research Promotion Fund of the Japan Private School Promotion Foundation and Research on Health Sciences Focusing on Drug Innovation from Japan Health Sciences Foundation.

  • DOI: 10.1124/jpet.103.059139.

  • ABBREVIATIONS: PAH, para-aminohippuric acid; hOAT, human organic anion transporter; PGF2α, prostaglandin F2α; rOAT, rat organic anion transporter; ES, estrone sulfate; oatp, organic anion-transporting polypeptide; HPLC, high-performance liquid chromatography; MRP, multidrug resistance-associated protein; DPBS, Dulbecco's modified phosphate-buffered saline.

    • Received August 26, 2003.
    • Accepted November 5, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 308 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 308, Issue 3
1 Mar 2004
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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Interactions of Human Organic Anion Transporters with Diuretics

Habib Hasannejad, Michio Takeda, Kentarou Taki, Ho Jung Shin, Ellappan Babu, Promsuk Jutabha, Suparat Khamdang, Mahmoud Aleboyeh, Maristela Lika Onozato, Akihiro Tojo, Atsushi Enomoto, Naohiko Anzai, Shinichi Narikawa, Xiu-Lin Huang, Toshimitsu Niwa and Hitoshi Endou
Journal of Pharmacology and Experimental Therapeutics March 1, 2004, 308 (3) 1021-1029; DOI: https://doi.org/10.1124/jpet.103.059139

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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Interactions of Human Organic Anion Transporters with Diuretics

Habib Hasannejad, Michio Takeda, Kentarou Taki, Ho Jung Shin, Ellappan Babu, Promsuk Jutabha, Suparat Khamdang, Mahmoud Aleboyeh, Maristela Lika Onozato, Akihiro Tojo, Atsushi Enomoto, Naohiko Anzai, Shinichi Narikawa, Xiu-Lin Huang, Toshimitsu Niwa and Hitoshi Endou
Journal of Pharmacology and Experimental Therapeutics March 1, 2004, 308 (3) 1021-1029; DOI: https://doi.org/10.1124/jpet.103.059139
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