Interactions of urate transporter URAT1 in human kidney with uricosuric drugs.

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Shin HJ, Takeda M, Enomoto A, Fujimura M, Miyazaki H, Anzai N, Endou H

Interactions of urate transporter URAT1 in human kidney with uricosuric drugs.

Nephrology (Carlton). 2011 Feb;16(2):156-62. doi: 10.1111/j.1440-1797.2010.01368.x.

PubMed ID

21272127 [ View in PubMed

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Abstract

AIM: Hyperuricaemia is a significant factor in a variety of diseases, including gout and cardiovascular diseases. The kidney plays a dominant role in maintaining plasma urate levels through the excretion process. Human renal urate transporter URAT1 is thought to be an essential molecule that mediates the reabsorption of urate on the apical side of the proximal tubule. In this study the pharmacological characteristics and clinical implications of URAT1 were elucidated. METHODS: Madin-Darby canine kidney (MDCK) cells stably expressing URAT1 (MDCK-URAT1) were established and examined the interactions of URAT1 with various drugs such as benzbromarone and its metabolites including 6-hydroxybenzbromarone, angiotensin-converting enzyme inhibitors, non-steroidal anti-inflammatory drugs and urate transport inhibitors including E3040 and probenecid. RESULTS: MDCK-URAT1 cells exhibited a time- and dose-dependent increase in urate uptake, with a Km value of 570.7 micromol/L. When an URAT1-green fluorescent protein fusion protein construct was expressed in MDCK cells, the protein was sorted mainly to the apical side of the membrane. The drugs except for captoril dose-dependently inhibited urate uptake mediated by URAT1, with half maximal inhibitory concentration (IC(50) ) values ranging 0.05-716 micromol/L. CONCLUSION: Comparing these IC(50) values with intratubular concentrations of unbound drugs in humans, it is thought that URAT1 is a target molecule of uricosuric drugs, including 6-hydroxybenzbromarone, probenecid, indomethacin and salicylate, to inhibit urate reabsorption in vivo. In addition, a cell line that stably expressing URAT1 could be a useful tool for the development of uricosuric drugs.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Sulfinpyrazone	Solute carrier family 22 member 12	Protein	Humans	Yes	Inhibitor	Details

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Probenecid	Solute carrier family 22 member 12	Protein	Humans	Unknown	Inhibitor	Details