1. Pharmacokinetics and metabolism of allopurinol riboside.
- Author
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Shapiro TA, Were JB, Danso K, Nelson DJ, Desjardins RE, and Pamplin CL 3rd
- Subjects
- Adolescent, Adult, Allopurinol adverse effects, Allopurinol blood, Allopurinol pharmacokinetics, Allopurinol urine, Antiprotozoal Agents adverse effects, Antiprotozoal Agents blood, Antiprotozoal Agents urine, Double-Blind Method, Drug Evaluation, Half-Life, Humans, Least-Squares Analysis, Male, Middle Aged, Oxypurinol blood, Purines blood, Ribonucleosides adverse effects, Ribonucleosides blood, Ribonucleosides urine, Allopurinol analogs & derivatives, Antiprotozoal Agents pharmacokinetics, Ribonucleosides pharmacokinetics
- Abstract
There are no safe and effective oral drugs to treat leishmaniasis and Chagas' disease. The safety, pharmacokinetics, and metabolism of single and multiple oral doses of allopurinol riboside, an investigational antiparasitic agent, were evaluated in a randomized, double-blinded, placebo-controlled study in 32 healthy male volunteers, at levels up to 25 mg/kg q.i.d. for 13 doses. No significant toxicity was detected. Allopurinol riboside peaks in plasma 1.6 hours after administration, has an elimination half-life of 3 hours, and steady-state concentrations in the therapeutic range. However, in contrast to preclinical studies in dogs (plasma levels proportional to oral doses up to 200 mg/kg), we found that plasma levels were unexpectedly low and did not rise with increasing dose. Furthermore, allopurinol and oxypurinol (unanticipated metabolites) were detected at levels proportional to the dose of allopurinol riboside. We present a model that includes incomplete absorption, metabolism of residual drug by enteric flora, and absorption of bacterial metabolites to explain these findings in humans.
- Published
- 1991
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