Concentration-dependent mode of interaction of angiotensin II receptor blockers with uric acid transporter.
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.
Iwanaga
Takashi
T
Department of Molecular Biopharmaceutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamasaki, Noda, Chiba 278-8510, Japan.
Sato
Masanobu
M
Maeda
Tomoji
T
Ogihara
Toshio
T
Tamai
Ikumi
I
D047228:Angiotensin II Type 1 Receptor Blockers / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology; D027361:Organic Anion Transporters / Q000502:physiology*; D027701:Organic Cation Transport Proteins / Q000502:physiology*; D011718:Pyrazinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology; D014527:Uric Acid / Q000378:metabolism; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan; D014982:Xenopus laevis
D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; C491241:SLC22A12 protein, human; D013777:Tetrazoles; D014527:Uric Acid; D011718:Pyrazinamide; C005296:pyrazinoic acid; D000068756:Valsartan; C437965:olmesartan; D014633:Valine; D019808:Losartan