Metabolic studies of purine metabolism in the pig during the oral administration of guanine and allopurinol

Abstract

(1) Allopurinol and guanine, both separately and together, were fed over varying periods to diiferent groups of large white/landrace cross pigs. Although allantoin and not uric acid represented the end point of purine metabolism in this species, total urinary purine excretion approximated that of a man of equivalent weight on a purine-free diet. No abnormality in the handling of guanine was found, up to 50 per cent of an exogenous load being absorbed, metabolized and rapidly excreted in the urine as allantoin. (2) Allopurinol alone, in increasing dosage, was capable of total saturation of the enzyme xanthine oxidase at high dosage levels, but produced only slight reduction in total purine excretion at any dosage. Allopurinol riboside was the principal urinary metabolite, increasing with increasing allopurinol dosage, even at dosages above enzyme saturation levels, when oxipurinol excretion had levelled off. Xanthine replaced allantoin as the principal urinary purine metabolite during allopurinol therapy but, despite saturation of the xanthine oxidase, allantoin excretion did not fall to zero and hypoxanthine excretion was not increased. Allopurinol also had an effect on pyrimidine excretion in the pig as indicated by increased urinary orotic acid and orotidine levels, an effect not eliminated when guanine was given together with allopurinol. (3) Combined therapy with allopurinol and guanine produced three additional effects to those when allopurinol was given alone, (a) Allopurinol reduced substantially the considerable increase in total purine excretion resulting from guanine alone, a finding difficult to explain on the basis of feedback inhibition of de novo purine synthesis. (b) Urinary hypoxanthine excretion increased and at the same time allopurinol riboside excretion decreased substantially, suggesting competitive inhibition of allopurinol riboside formation as mediated by the enzyme purine nucleoside phosphorylase. (c) Xanthine was again the principal urinary metabolite, but at levels in excess of its solubility, so that coprecipitation with oxipurinol occurred in the renal tubules causing a considerable degree of renal dysfunction. Crystals were not found in any other tissue, including muscle, so that no evidence of guanine gout was noted, nor any other abnormality of purine metabolism which could be related to leg weakness in pigs.