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Pharmacokinetics and metabolism of allopurinol riboside
Author(s) -
Shapiro Theresa A,
Were Joab B O,
Danso Kwame,
Nelson Donald J,
Desjardins Robert E,
Pamplin Charles L
Publication year - 1991
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.1991.61
Subject(s) - allopurinol , pharmacokinetics , pharmacology , oral administration , absorption (acoustics) , medicine , chemistry , physics , acoustics
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. Clinical Pharmacology and Therapeutics (1991) 49, 506–514; doi: 10.1038/clpt.1991.61