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Pharmaceutical Research

, Volume 25, Issue 3, pp 639–646 | Cite as

Involvement of Uric Acid Transporters in Alteration of Serum Uric Acid Level by Angiotensin II Receptor Blockers

  • Masanobu Sato
  • Takashi Iwanaga
  • Hideaki Mamada
  • Toshio Ogihara
  • Hikaru Yabuuchi
  • Tomoji Maeda
  • Ikumi Tamai
Research Paper

Abstract

Purpose

To examine the mechanisms of the alteration of serum uric acid level by angiotensin II receptor blockers (ARBs), the effects of ARBs on renal uric acid transporters, including OAT1, OAT3, OAT4, and MRP4, were evaluated.

Materials and Methods

Uptakes of uric acid by OAT1-expressing Flp293 cells, by Xenopus oocytes expressing OAT3 or OAT4, and by membrane vesicles from Sf9 cells expressing MRP4 were evaluated in the presence or absence of ARBs.

Results

All ARBs inhibited uptake of uric acid or estrone-3-sulfate by OAT1, OAT3 and OAT4 in concentration dependent manners. Among them, the IC50 values of valsartan, olmesartan and pratosartan for OAT3 were comparable to clinically observed unbound maximum plasma concentration of ARBs. Candesartan, losartan, and telmisartan inhibited ATP-dependent uptake of uric acid by MRP4 at 10 μM. The IC50 value of losartan for MRP4 was comparable to the estimated kidney tissue concentration of losartan. No ARBs showed trans-stimulatory effects on the uptake of estrone-3-sulfate by OAT4.

Conclusion

Valsartan, olmesartan, and pratosartan could inhibit the OAT3-mediated uric acid secretion in clinical situations. Furthermore losartan could inhibit ATP-dependent uric acid secretion by MRP4. These effects may explain partially the alteration of serum uric acid level by ARBs.

Key words

angiotensin II receptor blockers kidney MRP4 OAT uric acid transporter 

Abbreviations

ARB

angiotensin II receptor blocker

E13S

estrone-3-sulfate

MRP

multidrug resistance-associated protein

OAT

organic anion transporter

SUA

serum uric acid

URAT1

uric acid transporter

Notes

Acknowledgment

This study was supported in part by a Grant in Aid for Scientific Research from The Ministry of Education, Culture, Sports, Science, and Technology, Japan.

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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Masanobu Sato
    • 1
  • Takashi Iwanaga
    • 1
  • Hideaki Mamada
    • 1
  • Toshio Ogihara
    • 2
  • Hikaru Yabuuchi
    • 3
  • Tomoji Maeda
    • 1
  • Ikumi Tamai
    • 1
  1. 1.Department of Membrane Transport and Pharmacokinetics, Faculty of Pharmaceutical SciencesTokyo University of ScienceNodaJapan
  2. 2.Department of Geriatric MedicineOsaka University Graduate School of MedicineOsakaJapan
  3. 3.GenoMembrane, Inc.YokohamaJapan

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