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Research ArticleMETABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Concentration-Dependent Mode of Interaction of Angiotensin II Receptor Blockers with Uric Acid Transporter

Takashi Iwanaga, Masanobu Sato, Tomoji Maeda, Toshio Ogihara and Ikumi Tamai
Journal of Pharmacology and Experimental Therapeutics January 2007, 320 (1) 211-217; DOI: https://doi.org/10.1124/jpet.106.112755
Takashi Iwanaga
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Masanobu Sato
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Tomoji Maeda
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Toshio Ogihara
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Ikumi Tamai
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Abstract

Serum uric acid (SUA) is currently recognized as a risk factor for cardiovascular disease. It has been reported that an angiotensin II receptor blocker (ARB), losartan, decreases SUA level, whereas other ARBs, such as candesartan, have no lowering effect. Because the renal uric acid transporter (URAT1) is an important factor controlling the SUA level, we examined the involvement of URAT1 in those differential effects of various ARBs on SUA level at clinically relevant concentrations. This study was done by using URAT1-expressing Xenopus oocytes. Losartan, pratosartan, and telmisartan exhibited cis-inhibitory effects on the uptake of uric acid by URAT1, whereas at higher concentrations, only telmisartan did, and these ARBs reduced the uptake in competitive inhibition kinetics. On the other hand, candesartan, EXP3174 [2-n-butyl-4-chloro-1-[(2′-(1H-tetrazol-5-yl)biphenyl-4-yI)methyl]imidazole-5-carboxylic acid] (a major metabolite of losartan), olmesartan, and valsartan were not inhibitory. Preloading of those ARBs in the oocytes enhanced the URAT1-mediated uric acid uptake, showing a trans-stimulatory effect. The present study is a first demonstration of the differential effects of ARBs on URAT1 that some ARBs are both cis-inhibitory and trans-stimulatory, depending on concentration, whereas others exhibit either a trans-stimulatory or cis-inhibitory effect alone, which could explain the clinically observed differential effects of ARBs on SUA level. Furthermore, it was found that such differential effects of ARBs on URAT1 could be predicted from the partial chemical structures of ARBs, which will be useful information for the appropriate use and development of ARBs without an increase of SUA.

Footnotes

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.106.112755.

  • ABBREVIATIONS: SUA, serum uric acid; ARB, angiotensin II receptor blocker; URAT1, uric acid transporter; PZA, pyrazinecarboxylic acid; DMSO, dimethyl sulfoxide; EXP3174, (2-n-butyl-4-chloro-1-[(2′-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic acid.

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

    • Received August 19, 2006.
    • Accepted October 12, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 377 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 377, Issue 2
1 May 2021
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Research ArticleMETABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Concentration-Dependent Mode of Interaction of Angiotensin II Receptor Blockers with Uric Acid Transporter

Takashi Iwanaga, Masanobu Sato, Tomoji Maeda, Toshio Ogihara and Ikumi Tamai
Journal of Pharmacology and Experimental Therapeutics January 1, 2007, 320 (1) 211-217; DOI: https://doi.org/10.1124/jpet.106.112755

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Research ArticleMETABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Concentration-Dependent Mode of Interaction of Angiotensin II Receptor Blockers with Uric Acid Transporter

Takashi Iwanaga, Masanobu Sato, Tomoji Maeda, Toshio Ogihara and Ikumi Tamai
Journal of Pharmacology and Experimental Therapeutics January 1, 2007, 320 (1) 211-217; DOI: https://doi.org/10.1124/jpet.106.112755
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