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Abstract Number: 2963

The URAT1 Uric Acid Transporter Is Important in Uric Acid Homeostasis and Its Activity May be Altered in Gout Patients and in Drug-Induced Hyperuricemia

Philip K. Tan, Sha Liu and Jeffrey N. Miner, Ardea Biosciences, Inc., San Diego, CA

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: gout, hyperuricemia and uric acid, Kidney

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Session Information

Session Title: Metabolic and Crystal Arthropathies II: Mechanisms of Disease

Session Type: Abstract Submissions (ACR)

Background/Purpose: Gout results from chronic hyperuricemia. Most gout patients exhibit an increased renal reabsorption of uric acid which leads to elevated levels of serum uric acid (SUA). SUA levels are controlled in part through URAT1, a transporter that is essential for the renal reabsorption of uric acid. Our current research suggests that the renal uric acid reabsorption system is more completely saturated in normal healthy individuals but not in gout patients. We hypothesize that this difference may be due to differences in URAT1 activity, and present evidence that in gout patients as well as in hyperuricemia induced by certain drugs, the activity of uric acid transport by URAT1 is altered by the presence of other URAT1 substrates.

Methods: An analysis based on data from 4 Phase I/Ib studies, in which xanthine oxidase inhibitors (XOI) were given to either normal healthy volunteers (NHV) or gout patients, was conducted. The relationship between change in reabsorption of uric acid versus baseline reabsorption, as well as reabsorption of uric acid versus SUA, was examined. Uric acid transport activity of URAT1 was measured in HEK-293T cells transiently transfected with URAT1 in the absence or presence of salicylate, nicotinate, and other URAT1 substrates.

Results: From the SUA lowering effect of XOI treatment, gout patients experienced a greater change in reabsorption compared to NHV.  This indicates that in gout patients the reabsorption of uric acid may be more responsive to changes in SUA levels, and that in NHV the reabsorption of uric acid is less responsive and hence more saturated.  URAT1 transported uric acid with an affinity (equilibrium dissociation constant or Kd) of 154 µM. At 500 µM uric acid, the uric acid transport activity of URAT1 was greater than 90% of the maximal activity, approaching saturation for total transport activity.  Therefore, URAT1 is highly saturated for transport of uric acid at levels present in NHV (at or below 6.8 mg/dL or 408 µM), and the total transport activity of uric acid by URAT1 is reduced slightly upon physiologically-relevant reductions of uric acid, similar to the highly saturated renal reabsorption of uric acid observed in NHV.  However, in the presence of other URAT1 substrates such as salicylate, URAT1 transported uric acid with a 2- to 4-fold lower affinity (Kdwas increased), and at 500 µM uric acid, the uric acid transport activity of URAT1 was around 60% of the maximal activity.

Conclusion: The presence of other substrates leads to greater reductions in total uric acid transport by URAT1 as uric acid levels are reduced, as seen with the less saturated and more responsive renal reabsorption of uric acid in gout patients. The reabsorption profiles before and after XOI treatment in NHV or gout patients can be mimicked by the activity of the uric acid reabsorption transporter URAT1 in vitro, in the absence or presence of other URAT1 substrates, respectively.  The results suggest the the possibility that the enhanced reabsorption of uric acid in gout patients and in drug-induced hyperuricemia may be due to the presence of other URAT1 substrates that alter the uric acid transport kinetics of URAT1, which may lead to, or sustain, hyperuricemia.


Disclosure:

P. K. Tan,

Ardea Biosciences, Inc.,

3;

S. Liu,

AstraZeneca,

1,

Ardea Biosciences, Inc.,

3;

J. N. Miner,

AstraZeneca,

1,

Ardea Biosciences, Inc.,

3,

ARTA Bioscience,

6.

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