Uric acid transport, transporters, and their pharmacological targeting

Abstract

Knowledge of uric acid (UA) crystallopathies preceded the identification of this compound. How the body handles and transports UA proved even more elusive. Over several decades, advances in molecular phenotyping have illuminated this hitherto nebulous field. Closely parallel to the characterization of the transport mechanisms of UA in the body was the development of drugs designed to manipulate UA levels. In this review, we highlight the study of UA transport and transporters. This is an evolving field, and we expect our knowledge of the transport mechanisms to both widen and deepen further. We focus on the best‐characterized transporters rather than an exhaustive catalog of all suspected transporters. We review the established and novel compounds that modulate UA transport.

Discovery of a Novel Thienopyrimidine Compound as a Urate Transporter 1 and Glucose Transporter 9 Dual Inhibitor with Improved Efficacy and Favorable Druggability

“…The majority of uric acid exists as urate ions at physiological pH (∼7.4), which cannot freely traverse the cellular phospholipid bilayer . Consequently, the reabsorption and secretion of uric acid rely on various urate transporters. , During renal excretion, the primary reabsorption transporters are urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9), which serve as major determinants of SUA levels and of gout development. − …”

Unique Binding Sites of Uricosuric Agent Dotinurad for Selective Inhibition of Renal Uric Acid Reabsorptive Transporter URAT1

“…Molecularly, URAT1 (SLC22A12), OAT4 (SLC22A11), OAT10 (SLC22A13) in apical membrane and GLUT9 (SLC2A9) in basolateral membrane of tubular epithelial cells play roles of UA reabsorption. UA secretion is considered to be mediated by basolateral OAT1 (SLC22A6), OAT3 (SLC22A8) and OAT2 (SLC22A7), and apical BCRP (ABCG2), MRP4 (ABCC4), and NPT1 (SLC17A3) (Adomako and Moe, 2023). URAT1, a major pharmacological target transporter for uricosuric agents, belongs to the organic anion transporter OAT family.…”

Semiempirical Approach to the Fukui Function Analysis of Uric Acid under Different pH Conditions

“…Physiologically, only 10% of uric acid is excreted in urine, so it is not fully considered a disposal metabolic product . Clinically, uric acid is associated with a great number of pathologies. − It is seen as a physiological antioxidant in the extracellular environment while at the intracellular level it always acts as an oxidant . Therefore, this compound presents a kind of paradoxical duality of its functionality.…”