Involvement of uric acid transporters in alteration of serum uric acid level by angiotensin II receptor blockers.
OBJECTIVE
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.


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 microM. 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.


CONCLUSIONS
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.
Department of Membrane Transport and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamasaki, Noda, Chiba 278-8510, Japan.
Masanobu
M
Sato
Takashi
T
Iwanaga
Hideaki
H
Mamada
Toshio
T
Ogihara
Hikaru
H
Yabuuchi
Tomoji
T
Maeda
Ikumi
I
Tamai
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004970:Estrone / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D007313:Insecta; D007700:Kinetics; D026901:Membrane Transport Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009865:Oocytes; D027362:Organic Anion Transport Protein 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors / Q000378:metabolism; D014162:Transfection; D014527:Uric Acid / Q000097:blood / Q000378:metabolism*; D014982:Xenopus laevis
D047228:Angiotensin II Type 1 Receptor Blockers; D004970:Estrone; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; D014527:Uric Acid; C073492:ABCC4 protein, human; C427207:SLC22A11 protein, human; C498886:SLC22A9 protein, human; C114338:organic anion transport protein 3; C017296:estrone sulfate