TY - JOUR
T1 - Involvement of uric acid transporters in alteration of serum uric acid level by angiotensin II receptor blockers
AU - Sato, Masanobu
AU - Iwanaga, Takashi
AU - Mamada, Hideaki
AU - Ogihara, Toshio
AU - Yabuuchi, Hikaru
AU - Maeda, Tomoji
AU - Tamai, Ikumi
N1 - Funding Information:
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.
PY - 2008/3
Y1 - 2008/3
N2 - 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.
AB - 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.
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U2 - 10.1007/s11095-007-9401-6
DO - 10.1007/s11095-007-9401-6
M3 - Article
C2 - 17674156
AN - SCOPUS:40549090278
SN - 0724-8741
VL - 25
SP - 639
EP - 646
JO - Pharmaceutical Research
JF - Pharmaceutical Research
IS - 3
ER -