Allopurinol riboside

By contrast, when allopurinol riboside (11.19), a metabolite of allopuri-nol and an antiparasitic agent, is administered orally to humans, the drug is incompletely absorbed. The residual fraction is then extensively metabolized by the enteric flora to produce metabolites that are absorbed [41], Bacterial metabolism proceeds by cleavage to allopurinol, a reaction that apparently occurs only in the intestine. Although the examples described pertain to different animal species, it is clear that small structural changes can elicit major differences in metabolism. 

Nucleoside phosphotransferase Flagellated protozoa Allopurinol riboside and formycin B... 

Were JB, Shapiro TA. Effects of probenecid on the pharmacokinetics of allopurinol riboside. Antimicrob Agents Chemother 1993 37 1193-1196. 

Leishmaniasis Leishmania donovani, L tropica, L. mexicana, L. brasiliensis Pentostam, glucantime, urea stibamine, pentamidine, WR-6026, al-lopurinol, allopurinol riboside, amphotericin B... 

This has been translated into clinical benefits. There have been several reports of the efficacy of allopurinol in visceral leishmaniasis and one study using allopurinol riboside in cutaneous leishmaniasis. More recently, a controlled study in Colombia has documented the efficacy of allopurinol in cutaneous leishmaniasis (20). In this study the cure rate of allopurinol was 80% compared to 74% using allopurinol and glucantime together. The cure rate of glucantime alone was 36%. A similar study of the efficacy of allopurinol in chronic asymptomatic Chagas disease showed that allopurinol in doses of 600 or 900 mg day was equal efficacy to nifurotimox or benznidazole (21). 

B) Allopurinol riboside is a potent inhibitor of mitochondrial electron transfer... 

A study in 3 healthy subjects found that probenecid halved the clearance, increased the peak plasma levels and AUC, and extended the half life of allopurinol riboside. In some circumstances such an interaction may be advantageous as there is some evidence that the cure rate of American trypanosomiasis (Chagas disease) and cutaneous leishmaniasis is better when the two drugs are used together. ... 

Were JBO, Slwpiro TA. Effects of probenecid on the phannacokinetics of allopurinol riboside Antimicrob Agents Chemoiher (1993) 37,1193-6. 

Saenz RE, Paz HH Johnson CM, Ivfarr JJ, Nelson DJ, Pattishall KH, R ers MD. Treatment of American cutaneous leishmaniasis with orally administered allopurinol riboside J Infect Di5(1989) 160,153-8. 

Probenecid and benzbromarone increase the renal excretion of oxipurinol, the active metabolite of allopurinol, but this probably does not alter clinical efficacy. Theoretically, the use of uricosuric drugs with allopurinol could lead to uric acid precipitation in the kidneys and therefore maintenance of a high urine output is recommended when allopurinol is given by injection. Probenecid markedly increases the serum levels of allopurinol riboside, which may be advantageous in some circumstances. 

Growth of the Leishmanias is also inhibited by the antibiotic, formycin B, which is an isomer of allopurinol riboside from which it differs only in being a [4,3-rf] instead of a [3,4- /] pyrazolopyrimidine. This antibiotic is curative in hamsters infected with L. donovani infections. Its curative activity depends on phosphorylation by the protozoa, a reaction which mammalian cells do not carry out (Carson and Chang, 1981). 

Allopurinol has been used for 16 years at doses ranging from 200 to 800 mg/day for the control of primary and secondary hyperuricemia. At the most commonly used doses of allopurinol (300-400 mg/ day) about 70% of the allopurinol is oxidized to oxipurinol, which is excreted in the urine. Urinary allopurinol and allopurinol riboside each account for about 10% of the dose. Since the degree of xanthine oxidase inhibition is dose-related, not only the oxidation of hypoxanthine and xanthine to uric acid, but also the oxidation of allopurinol to oxipurinol might be expected to be strongly inhibited at high doses of allopurinol. This would lead to increased levels of allopurinol, as well as allopurinol riboside, in plasma and urine. The extent to which this phenomenon occurs was investigated in several laboratory animal species and in man. 

A hyperuricemic individual who had taken 1500 mg of allopurinol (21 mg/kg) as a single daily dose for over one year showed peak plasma levels of allopurinol of 6.9 pg/ml, and of allopurinol riboside of 9.1 Mg/ml at 3 hrs oxipurinol varied between 16 and 29 Mg/rol over the course of a day. Urine contained 15% of the dose as allopurinol, 42% as allopurinol riboside, and 37% as oxipurinol. 

Allopurinol was given orally up to fifty times maximum human therapeutic doses without side effects. Allopurinol and oxipuri-nol appeared to be handled similarly by pig (798) and human kidney (in contrast to rat, mouse and dog) (9) Xanthine oxidase was maximally inhibited by allopurinol at 2.2 mmol (300 mg)/kg/day with no further increase in oxipurinol and xanthine excretion at higher doses. No limit, however, was found for the rmation of allopurinol riboside. 9k% of radioactivity om (6- C) allopurinol was recovered from the urine and no C incorporation was detected in tissue nucleotides. 

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