Pharmacological Evaluation of Dotinurad, a Selective Urate Reabsorption Inhibitor

The Journal of Pharmacology and Experimental Therapeutics
Tetsuya TaniguchiTakashi Iwanaga

Abstract

The effect of dotinurad [(3,5-dichloro-4-hydroxyphenyl)(1,1-dioxo-1,2-dihydro-3H-1λ6-1,3-benzothiazol-3-yl)methanone] was compared with that of commercially available uricosuric agents-namely, benzbromarone, lesinurad, and probenecid. Its effect on urate secretion transporters was evaluated using probe substrates for respective transporters. Dotinurad, benzbromarone, lesinurad, and probenecid inhibited urate transporter 1 (URAT1) with IC50 values of 0.0372, 0.190, 30.0, and 165 μM, respectively. Dotinurad weakly inhibited ATP-binding cassette subfamily G member 2 (ABCG2), organic anion transporter 1 (OAT1), and OAT3, with IC50 values of 4.16, 4.08, and 1.32 μM, respectively, indicating higher selectivity for URAT1. The hypouricemic effects of dotinurad and benzbromarone were evaluated in Cebus monkeys. Dotinurad, at doses of 1-30 mg/kg, concomitantly decreased plasma urate levels and increased fractional excretion of urate (FEUA) in a dose-dependent manner. On the contrary, benzbromarone, at a dose of 30 mg/kg, showed a modest effect on plasma urate levels. The inhibitory effect of dotinurad on urate secretion transporters was evaluated in Sprague-Dawley rats, with sulfasalazine and adefovir as probe substrates of ABCG2 and OAT...Continue Reading

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Citations

Apr 25, 2020·Expert Opinion on Drug Discovery·Naoyuki OtaniNaohiko Anzai
Dec 4, 2019·Pharmacology Research & Perspectives·Keisuke MotokiTetsuo Ohashi
Jan 1, 2020·Clinical and Experimental Nephrology·Hiroshi NakataniTetsuo Ohashi
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Dec 27, 2019·Clinical and Experimental Nephrology·Tatsuo HosoyaTetsuo Ohashi
Nov 3, 2020·Biological & Pharmaceutical Bulletin·Hiroshi ArakawaIkumi Tamai
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May 1, 2021·Expert Opinion on Pharmacotherapy·Tomohiko IshikawaTatsuo Hosoya
Jul 3, 2021·Pharmaceutics·Péter TátraiPéter Krajcsi
Sep 12, 2021·European Heart Journal·Eun Ha KangSeoyoung C Kim

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