Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018099 (gout)
 5,192 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Unknown concentrations of orotic acid can be measured by competition with a known amount of [carboxyl-14C]orotic acid for reaction with a limiting amount of phosphoribosylpyrophosphate in the presence of orotate phosphoribosyltransferase and orotidine monophosphate decarboxylase. The dilution of the specific radioactivity in the product 14CO2 is a sensitive and accurate measure of the amount of orotic acid present in the sample. Orotidine can also be determined after hydrolytic cleavage to orotic acid. The method was used to measure orotic acid and orotidine in urine samples from newborns, healthy controls and patients with gout or deficiency of hypoxanthine-guanine phosphoribosyltransferase receiving allopurinol. Urinary excretion of orotic acid and orotidine in newborns was similar whether the infants were breast-fed or received milk powder. The excretion of orotidine was increased in all patients receiving allopurinol. After allopurinol administration orotic acid excretion was increased in gouty patients but close to normal values in patients with deficiency of hypoxanthine-guanine phosphoribosyltransferase. The results are discussed in relation to the mechanism by which allopurinol inhibits pyrimidine metabolism.
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PMID:The urinary excretion of orotic acid and orotidine, measured by an isotope dilution assay. 36 97

The purine analogue, allopurinol, has been in clinical use for more than 30 years as an inhibitor of xanthine oxidase (XO) in the treatment of hyperuricemia and gout. As consequences of structural similarities to purine compounds, however, allopurinol, its major active product, oxypurinol, and their respective metabolites inhibit other enzymes involved in purine and pyrimidine metabolism. Febuxostat (TEI-6720, TMX-67) is a potent, non-purine inhibitor of XO, currently under clinical evaluation for the treatment of hyperuricemia and gout. In this study, we investigated the effects of febuxostat on several enzymes in purine and pyrimidine metabolism and characterized the mechanism of febuxostat inhibition of XO activity. Febuxostat displayed potent mixed-type inhibition of the activity of purified bovine milk XO, with Ki and Ki' values of 0.6 and 3.1 nM respectively, indicating inhibition of both the oxidized and reduced forms of XO. In contrast, at concentrations up to 100 muM, febuxostat had no significant effects on the activities of the following enzymes of purine and pyrimidine metabolism: guanine deaminase, hypoxanthine-guanine phosphoribosyltransferase, purine nucleoside phosphorylase, orotate phosphoribosyltransferase and orotidine-5'-monophosphate decarboxylase. These results demonstrate that febuxostat is a potent non-purine, selective inhibitor of XO, and could be useful for the treatment of hyperuricemia and gout.
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PMID:Selectivity of febuxostat, a novel non-purine inhibitor of xanthine oxidase/xanthine dehydrogenase. 1569 61