Overview of the pharmacokinetics and pharmacodynamics of URAT1 inhibitors for the treatment of hyperuricemia and gout

ABSTRACT

Introduction

Hyperuricemia is a common metabolic disease, which is a risk factor for gouty arthritis and ureteral stones and may also lead to cardiovascular and chronic kidney disease (CDK). Therefore, hyperuricemia should be treated early. Xanthine oxidase inhibitors (XOIs) and uricosuric agents (UAs), which target uric acid, are two types of medications that are used to treat gout and hyperuricemia. XOIs stop the body from producing excessive uric acid, while UAs eliminate it rapidly via the kidneys. Urate transporter 1 (URAT1) belongs to the organic anion transporter family (OAT) and is specifically localized to the apical membrane of the epithelial cells of proximal tubules. Unlike other organic anion transporter family members, URAT1 identifies and transports organic anions that are primarily responsible for urate transport.

Areas covered

This article reviews the pharmacokinetics and pharmacodynamics of the existing URAT1 inhibitors to serve as a reference for subsequent drug studies.

Expert opinion

The URAT1 inhibitors that are currently used as clinical drugs mainly include dotinurad, benzbromarone, and probenecid. Results indicate that RDEA3170 may be the most promising inhibitor, in addition to SHR4640, URC-102, and MBX-102, which are in the early stages of development.

KEYWORDS:

• URAT1
• hyperuricemia
• gout
• pharmacokinetics
• pharmacodynamics
• dotinurad
• benzbromarone

Article highlights

• Review of beneficial properties and mechanisms of URAT1 inhibitors in the treatment of hyperuricemia and gout.

• Introduction of URAT1 inhibitors in terms of the chemical structure, specific mechanism, and effective dose.

• Review of the pharmacokinetics and pharmacodynamics of the existing URAT1 inhibitors to serve as a reference for subsequent drug studies.

• The side effects of URAT1 inhibitors are described.

• Discussion of current challenges and future prospects of URAT1 inhibitors to anti-hyperuricemia and anti-gout agents.

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author Contribution Statement

Z Hou: Writing-original draft; A Ma: Writing-review & editing; J Mao: Writing-review & editing; D Song: Writing-review & editing; X Zhao supervised the project and directed the research. All authors reviewed the manuscript.

Additional information

Funding

This work was supported by Young and Middle-Aged Teachers’ Career DevelopmentSupport Project of Shenyang Pharmaceutical University (ZQN2019005).