Uricosuric and Hypo-Uricemic Activity

Purpose and Rationale Synthesis of uric acid primarily occurs in the liver, but the kidney has an important role in the pathophysiology of hyperuricemic syndromes. Because uric acid is poorly soluble, excessive amounts in the circulation may precipitate out into the tissues, particularly the joints, resulting in a painful arthropathy (“gout”). In humans, this condition is usually the result of faulty tubular transport of urate, resulting in increased net reabsorption. Attempts to treat hyperuricemia with tubular transport inhibitors (theoretically increasing urinary excretion of urate) frequently exacerbate the condition because tubular transport is bi-directional; reduction of net uric acid synthesis by the inhibition of xanthine oxidase is the preferred therapeutic approach. Furthermore, in renal hypoxic conditions, xanthine oxidase contributes to renal injury by the generation of oxygen free radicals and xanthine oxidase inhibition has been shown to be useful in such conditions (Shinosaki and Yonetani 1991; Rhoden et al. 2000; Terkeltaub et al. 2006). Xanthine oxidase catalyzes the oxidation of hypoxanthine and xanthine to uric acid. Xanthine oxidase is a complex metalloflavoprotein containing one molybdenum, one FAD, and two iron-sulfur centers of the ferredoxine type in each of its two independent subunits. Usually, the enzyme is isolated from cow’s milk. The enzyme is inhibited by allopurinol and related compounds. The production of uric acid from the substrate (xanthine) can be determined by measuring the change in optical density in the UV range.