Uricosuric agents, such as benzbromarone and probenecid, are of limited use due to the risk of their drug-induced liver injury (DILI) and drug-drug interactions (DDIs). We have developed a novel uricosuric agent, dotinurad, that has a potent pharmacological effect while avoiding these risks. Inhibitory effect of dotinurad on mitochondrial function, an index of hepatotoxicity, was weak and there was no observation suggesting a risk of DILI taking into consideration the clinical dose or exposure. According to the guideline, dotinurad was assessed not to have a risk of DDI caused by inhibition of CYPs or transporters.
In confirmatory phase II and long-term studies, dotinurad decreased serum urate levels at low doses and almost patients receiving maintenance dose (2 or 4 mg) achieved a serum urate level ≤ 6.0 mg/dL. Moreover, there was no finding to raise safety concern including liver injury. Dotinurad is characterized as a selective urate reabsorption inhibitor (SURI), which is defined as a potent URAT1 inhibitor with minimal effect on urate secretion transporters, including ABCG2 and OAT1/3. Our findings suggested that SURI is promising in view of superior hypouricemic effect, lower DDIs risk, and lower inhibitory effect on excretion of substances such as indoxyl sulfate known as uremic toxin.
Dotinurad has been approved in Japan, and described in the Guidelines for Management of Hyperuricemia and Gout 3rd edition, 2022 supplement version with its pharmacological classification as an SURI. Its efficacy and safety will be further evaluated in the clinical use.