Allopurinol metabolic studies

Ellon GB, Kovensky A, HItchIngs GH. Metabolic studies of allopurinol, an Inhibitory of xanthine oxidase. Blochem Pharmacol 1965 15 863-880. 

Metabolic Studies of Allopurinol, An Inhibitor of Xanthine Oxidase, Biochem. Pharmacol. (1966) 15, 863-880. 

Simmonds, H. A., Hatfield, P. J., Cameron, J.St. Metabolic studies of purine metabolism in the pig during the oral administration of guanine and allopurinol. Biochem. Pharmacol. 22 2537 (1973). 

METABOLIC STUDIES OF HIGH DOSES OF ALLOPURINOL IN HUMANS... 

Allopurinol Metabolism In Man - There are scattered reports of the use of allopurinol at doses of 900 mg ( 12 mg/kg) per day or higher (Sweetman, 1968 Rundles, 1966). The proposed use of high doses of allopurinol to improve the chemotherapeutic index of 5-fluorouracil (Schwartz, 1980) and also to treat the parasitic disease, leishmaniasis, gave impetus to the present metabolic study. 

S. Sved and L. Wilson. Analysis of allopurinol and oxipurinol in plasma and its application to metabolic studies. Biopharmaceutics and Drug Disposition, 1 111 (1980). 

The best known xanthine oxidase inhibitor is allopurinol (248), first synthesized by Robins (56JA784) and still the drug of choice for treatment of gouty arthritis. The metabolism of this drug as well as its other effects have been extensively studied. 

The risk of bone marrow depression by cytostatic drugs is potentiated by allopurinol, which also appears to potentiate the therapeutic effect of purine cytostatic drugs, since it competitively inhibits their metabolic breakdown. Studies in animals suggest that this reaction occurs only with oral mercaptopurine (28), although there is older evidence that the toxicity of cyclophosphamide and other cytostatic drugs can be increased by allopurinol (SED-9, 156). The danger of combining allopurinol with azathioprine has been confirmed by cases of bone marrow suppression, particularly in patients with impaired renal function (SEDA-16,114). 

One study has found that allopurinol, when administered orally to rats, antagonized the oxidative effects of manganese in the striatum and brainstem (Desole et al. 1994). The authors suggest that allopurinol, a xanthine oxidase inhibitor, may exert its protective effect by inhibiting both dopamine oxidative metabolism and xanthine oxidase-mediated production of reactive oxygen species. 

Allopurinol was synthesized in 1956 as part of a study of purine antagonists (88). It is well absorbed on oral administration, with peak plasma concentrations appearing within 1 hour. Decreases of uric acid can be observed within 24 to 48 hours. Excretion of allopurinol and its metabolite occurs primarily in the urine, with approximately 20% of a dose being excreted in the feces. Allopurinol is rapidly metabolized via oxidation and the formation of numerous... 

The manufacturer notes that allopurinol may inerease the exposure to didanosine by inhibiting xanthine oxidase, an enzyme involved in didanosine metabolism. This interaction has been studied for its therapeutic benefit. However, if the dose of didanosine is not redueed, there is the potential for an increase in didanosine adverse effeets. 

Uncertain. Allopurinol, a xanthine oxidase inhibitor, can block the conversion of methylxanthine to methylurie aeid, but this had no effeet on theophylline levels in two studies. One suggestion is that allopurinol inhibits the oxidative metabolism of theophylline by the liver. ... 

Evidence appears to be limited to a single case report and the studies in healthy subjects. The interaction only appears to be of moderate importance. Nevertheless, it would seem prudent to check for any signs of theophylline adverse effects (headache, nausea, tremor) during concurrent use, particularly in situations where the metabolism of the theophylline may already be reduced (other drugs or diseases), or where high doses of allopurinol are used. For mention that allopurinol may invalidate the results of phenotyping tests using caffeine, see Caffeine + Allopurinol ,... 

Probenecid appears to increase the renal excretion of the active metabolite of allopurinol, oxipurinol, while allopurinol is thought to inhibit the metabolism of probenecid. Allopurinol can increase the half-life and raise the serum levels of probenecid by about 50% and 20%, respectively. In another study, benzbromarone lowered the AUC of oxipurinol by about 40%, but did not affect allopurinol levels. ... 

There are several studies on the effect of allopurinol and its metabolic derivatives on orotate phosphoribosyltransferase and orotidylic acid decarboxylase [127-129]. The administration of allopurinol to rats results in an increased urinary excretion of orotic acid and orotidine [127,130,131], and in elevated activities of orotate phosphoribosyltransferase and orotidylic acid decarboxylase in erythrocytes [128,129]. Also, in man, the administration of allopurinol and oxipurinol leads to an increase in the specific activity of orotate phosphoribosyltransferase and orotidylic acid decarboxylase [129]. The enzymes were found to exist in a complex as three different molecular species with molecular weights of 55000, 80000 and 113 000 daltons. The larger forms of the complex were more stable than the smaller one. In the presence of allopurinol or oxipurinol ribonucleotides (but not the corresponding free bases) the largest, most stable species predominated [129]. 

Patients with chronic gouty arthritis unresponsive to allopurinol are generally dismissed as poor compliers. This paper presents studies in a middle-aged male with a 20-year history of gout in whom allopurinol in varying doses and combinations had proved ineffective in controlling either plasma uric acid levels or the gouty arthritis. The patient was studied on two separate occasions under Metabolic Ward conditions because the initial study on low dose allopurinol had failed to reduce plasma uric acid levels -they had in fact increased. 

The present comparative studies were undertaken to explore the possibility that the use of Thiopurinol a drug which does not induce xanthinuria, might have certain advantages over Allopurinol in the treatment of gout. Though we do not claim to have proven this, the absence of xanthinuria or any effect on pyrimidine metabolism in the form of orotidine or orotic aciduria, coupled with the finding that in the pig, tissue incorporation does not occur, are three points which we believe favour the possible increased use of this drug ... 

As xanthine oxidase activity has been demonstrated to occur in the rat kidney but not in monkeys 5) the net secretion observed in rat proximal tubules could be due to cellular rather than to transtubular secretion. The influence of urate synthesis on urate excretion was studied by clearance methods in rats anesthetized with pentobarbital. The animals were infused with hypoxan-thine (0.5 ug/min)a metabolic precursor of urate, or allopurinol, (5 ug/min), a xanthine-oxidase inhibitor. 

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