Background: Gout is a type of arthritis caused by the buildup of uric acid crystals in the joints, leading to inflammation and pain. Xanthine oxidase (XO) inhibitors, such as allopurinol (ALO) and febuxostat (FBX), are the current standard of care for lowering serum urate levels in patients with gout. Tigulixostat (TGX) is a potent and highly selective non-purine based XO inhibitor being investigated for the management of hyperuricemia in patients with gout.

Objectives: To evaluate the in vitro and in vivo preclinical efficacy of TGX, along with the effect of TGX on pyrimidine metabolism.

Methods: Bovine milk xanthine oxidase and rat plasma were used for in vitro xanthine oxidase assay. For evaluation of IC ₅₀ , bovine milk xanthine oxidase was incubated with xanthine in the presence and absence of the test compound at room temperature. Uric acid formation was determined by spectrophotometer. Potency in rat plasma was measured by xanthine/xanthine oxidase assay kit. IC ₅₀ of FBX and TGX in both studies were calculated with a non-linear best-fit regression model. In vivo studies, hypouricemic effect of FBX and TGX was evaluated in potassium oxonate (uricase inhibitor) induced hyperuricemia rat model. Rats were intraperitoneally injected with potassium oxonate (300 mg/kg) 1h before the test compound administration. Concentration of test compounds and uric acid were measured in plasma and liver. To test the effects on pyrimidine metabolism and kidney toxicity, ALO, FBX, and TGX at 100, 300 mg/kg or vehicle were orally administered to Balb/c mice. Blood samples were collected 24hr after drug administration and plasma concentration of orotic acid (OA), orotidine (OD), creatinine (Cr), and blood urea nitrogen (BUN) were measured.

Results: IC ₅₀ values of FBX and TGX in bovine milk were 0.003µM and 0.003µM, respectively. In rat plasma assay, IC ₅₀ were 0.154µM and 0.073µM, respectively. Both compounds showed a hypouricemic effect in potassium oxonate-pretreated rats which EC ₅₀ values of FBX and TGX were 0.34 μg/ml and 0.39 μg/ml, respectively. In normal Balb/c mice, plasma OD and OA increased 24hrs after administration of high dose (100 or 300mg/kg) of ALO, but remained unchanged after administration of FBX or TGX. FBX and TGX also showed no changes of Cr and BUN, the indicator of kidney toxicity.

Conclusion: In preclinical evaluation of efficacy, TGX inhibited XO enzyme activity and lowered uric acid at a level comparable to febuxostat. In addition, TGX, with no structural resemblance to purine base, does not affect the pyrimidine metabolism and its related kidney toxicity in mice.

REFERENCES: NIL

Acknowledgements: NIL.

Disclosure of Interests: None declared.