Indications
Topiroxostat is approved for the treatment of gout and hyperuricemia in Japan. It effectively manages these conditions by modulating uric acid levels within the body.
Pharmacodynamics
The primary mechanism of action for Topiroxostat involves the selective and time-dependent inhibition of xanthine oxidase. This competitive inhibition reduces the synthesis of uric acid, thereby decreasing the accumulation of insoluble urates and uric acid in tissues, plasma, and urine. Importantly, Topiroxostat has not been associated with QT prolongation.
Absorption
Upon oral administration of a 20 mg dose of Topiroxostat, the peak plasma concentration of 229.9 ng/mL is achieved approximately 0.67 hours post-dose. In preclinical studies involving male rats, the oral bioavailability of Topiroxostat was observed to be 69.6% following a single oral dose of 1 mg/kg.
Metabolism
Topiroxostat undergoes extensive hepatic metabolism primarily through hydroxylation and glucuronidation pathways. The initial hydroxylation by xanthine oxidase leads to the formation of 2-hydroxy topiroxostat, which retains inhibitory activity on the enzyme. Another significant metabolite is Topiroxostat N-oxide, detectable in both plasma and urine. The biotransformation to N1-and N2-glucuronide conjugates primarily occurs via UGT1A1, 1A7, and 1A9 enzymes, with UGT1A9 being the predominant pathway.
Mechanism of Action
Topiroxostat operates by inhibiting xanthine oxidase, an enzyme crucial in the uric acid synthesis pathway, which involves the conversion of hypoxanthine to xanthine and subsequently, xanthine to uric acid. Xanthine oxidase contains a molybdenum ion at its active site, functioning as a cofactor and undergoing a change in redox states during substrate interactions. Upon binding with substrates like hypoxanthine or xanthine, the enzyme facilitates hydroxylation, resulting in the reduction of the molybdenum ion from its hexavalent form, Mo(VI), to its tetravalent form, Mo(IV). The ion returns to its hexavalent state following the release of the hydroxylated substrate. Topiroxostat interacts with xanthine oxidase by engaging multiple amino acid residues within the solvent channel and forms a covalent bond with the Mo(IV) ion through an oxygen atom, creating a reaction intermediate. It also establishes hydrogen bonds with the Mo(VI) ion, indicating diverse inhibition mechanisms. The strong binding affinity of topiroxostat prolongs its association with the enzyme. The metabolite 2-hydroxy-topiroxostat, resulting from the hydroxylation of topiroxostat by xanthine oxidase, contributes to inhibition in a time and concentration-dependent manner. Additionally, Topiroxostat has been demonstrated to inhibit the ATP-binding cassette transporter G2 (ABCG2) in vitro. ABCG2 is a membrane protein involved in the renal reabsorption and intestinal excretion of uric acid.
