Ideal pharmacokinetic profile of dotinurad as a selective urate reabsorption inhibitor

Dotinurad, a novel selective urate reabsorption inhibitor (SURI), has potent inhibitory effects at low doses on the uptake of urate by urate transporter 1 (URAT1, solute carrier family 22 member 12 [SLC22A12]), localized at the apical membrane of renal proximal tubular cells. This study sought to cl...

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Veröffentlicht in:Drug metabolism and pharmacokinetics 2020-06, Vol.35 (3), p.313-320
Hauptverfasser: Omura, Koichi, Miyata, Kengo, Kobashi, Seiichi, Ito, Azusa, Fushimi, Masahiko, Uda, Junichiro, Sasaki, Tomomitsu, Iwanaga, Takashi, Ohashi, Tetsuo
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container_end_page 320
container_issue 3
container_start_page 313
container_title Drug metabolism and pharmacokinetics
container_volume 35
creator Omura, Koichi
Miyata, Kengo
Kobashi, Seiichi
Ito, Azusa
Fushimi, Masahiko
Uda, Junichiro
Sasaki, Tomomitsu
Iwanaga, Takashi
Ohashi, Tetsuo
description Dotinurad, a novel selective urate reabsorption inhibitor (SURI), has potent inhibitory effects at low doses on the uptake of urate by urate transporter 1 (URAT1, solute carrier family 22 member 12 [SLC22A12]), localized at the apical membrane of renal proximal tubular cells. This study sought to clarify the pharmacokinetic (PK) profile of dotinurad. In rats, monkeys, and humans, the apparent distribution volume (0.257, 0.205, and 0.182 L/kg, respectively) and oral clearance (0.054, 0.037, and 0.013 L·h−1·kg−1, respectively) of dotinurad were very low, whereas plasma and luminal concentrations were adequately maintained at high levels. In addition, species differences were scarcely observed with plasma protein binding of 99.4%. The main metabolite was dotinurad glucuronide (no specific metabolites in humans), and percentage excretion of unchanged dotinurad was low in all the investigated species. The risk of drug interaction with dotinurad was expected to be low, because it weakly inhibits metabolic enzymes such as cytochrome P450 (CYP). In conclusion, low-dose dotinurad exhibited excellent pharmacological effects as well as ideal PK properties as a SURI. [Display omitted]
doi_str_mv 10.1016/j.dmpk.2020.03.002
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subjects Animals
Benzothiazoles - administration & dosage
Benzothiazoles - blood
Benzothiazoles - pharmacokinetics
Dose-Response Relationship, Drug
Dotinurad
Haplorhini
Human mass balance study
Humans
Hyperuricemia
Life Sciences & Biomedicine
Male
Pharmacology & Pharmacy
Rats
Rats, Sprague-Dawley
Science & Technology
URAT1
Uric Acid - antagonists & inhibitors
Uric Acid - metabolism
Uricosuric agent
title Ideal pharmacokinetic profile of dotinurad as a selective urate reabsorption inhibitor
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