Induction of profound hypouricemia by a non-sedating thiobarbiturate

Abstract 5-[N-phenylcarboxamido]-2-thiobarbituric acid (merbarone) is a non-sedating derivative of thiobarbituric acid originally developed for anticancer use. In the initial clinical study, a profound reduction in serum uric acid was observed. In 20 patients who received five daily doses of merbarone ranging from 100 to 750 mg/m 2 , serum uric acid concentration was reduced from a mean pretreatment value of 5.7 ± 1.6 mg/dL to a mean lowest value of 1.3 ± 0.5 mg/dL. In most patients, the onset of the effect occurred with 24 hours and was maximal by 48 to 72 hours. Metabolic studies in two patients showed an increase in urinary uric acid excretion within 24 hours after initiation of drug treatment. A marked increase in fractional excretion of uric acid was sustained throughout the period of drug treatment. Urinary excretion of total oxypurines (xanthine and hypoxanthine) was increased twofold to threefold relative to baseline levels. Ultrafiltration studies showed that merbarone did not significantly displace binding of urate from albumin. When merbarone was incubated with xanthine oxidase in vitro, several reaction products were observed, including 2-oxo-2-desthio-merbarone and a compound with retention time similar to 4′-OH-merbarone. Both of these compounds have been described previously as metabolites of merbarone in human subjects. The parent drug and both metabolites were found to inhibit xanthine oxidase (K i = 41, 36, and 240 μmol/L, respectively). However, this inhibitory effect was substantially less potent than allopurinol (K i = 0.025 μmol/L). This study indicates that merbarone induces profound hypouricemia primarily by increasing uric acid excretion. Since urate binding to plasma protein is not affected, uricosuria is probably caused by a direct drug action on the renal tubule. Oxidation of merbarone by xanthine oxidase may be an important mechanism for drug metabolism in humans. Merbarone and both of its major metabolites inhibit xanthine oxidase in vitro. However, the magnitude of the increase in urinary oxypurine excretion is considerably less than that reported for allopurinol. Since merbarone does not cause adverse reactions at doses which induce marked hypouricemia, current studies are evaluating merbarone as treatment for hyperuricemia in patients who are intolerant of allopurinol.