FRI0403 Arhalofenate, a novel uricosuric agent, is an inhibitor of human URIC acid transporters

Background

It is estimated that the hyperuricemia in 80- 90% of gout patients is due to under excretion of uric acid. Uricouric drugs decrease serum uric acid by causing a reciprocal increase in uric acid excretion into urine. This occurs by inhibition of apical organic anion transporters/exchangers, including URAT1, OAT4 and OAT10, which are responsible for reabsoprtion of uric acid from the proximal renal tubule. Arhalofenate is a novel uricosuric agent in development for the treatment of hyperuricemia in patients with gout. In vitro profiling of the biologically active form of arhalofenate (arhalofenate acid) established that it is an inhibitor of uric acid transport mediated by URAT1, OAT4 and OAT10. Arhalofenate acid was found to be 8-20 fold more potent than probenecid. In addition, arhalofenate acid did not inhibit xanthine oxidase, another mechanism by which drugs can lower serum uric acid.

Objectives

To evaluate the basis for the uricosuric action of arhalofenate acid by assessing its inhibition of human renal urate transporters in vitro and to compare its effects with the currently available uricosuric agents.

Methods

The inhibition of the human urate transporters URAT1, OAT4 and OAT10 was determined by measuring the uptake of ¹⁴C-uric acid into human HEK293 cells transiently expressing the relevant transporter relative to the uptake into parental HEK293 cells.

Results

Arhalofenate acid inhibited urate transport by all three transporters tested with IC₅₀values of 92 μM for URAT1, 2.6 μM for OAT4 and 53 μM for OAT10. Probenecid showed much weaker inhibition of these same transporters with IC₅₀ values of 750 μM, 29 μM and 1.0 mM being observed with URAT1, OAT4 and OAT10, respectively. In contrast, benzbromarone was found to be an inhibitor of both URAT1 and OAT4 with IC₅₀ values of 0.30 μM and 1.5 μM, respectively, but was somewhat less potent against OAT10 (IC₅₀ of >3 μM). Arhalofenate was also found to be inactive toward xanthine oxidase.

Conclusions

Arhalofenate is a novel uricosuric agent that is converted in vivo to an inhibitor of multiple uric acid transporters which lacks xanthine oxidase activity. At doses studied in clinical trials the levels of arhalofenate acid found in human urine match or exceed the in vitro IC₅₀ value against these transporters. These results confirm the mode of action of arhalofenate as a uricosuric agent

Disclosure of Interest

None Declared