Pharmacokinetics and metabolism of allopurinol riboside.

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.

Pituitary and thyroid function in male cynomolgus monkeys.

In four male cynomolgus monkeys, serum thyroxine was 6.2 +/- 0.9 micrograms/dl, and triiodothyronine was 207 +/- 12 ng/dl (mean +/- SE). Kinetic studies using 131I-thyroxine and 125I-triiodothyronine showed that the disappearance of both hormones was non-linear and best fit a biexponential equation. The metabolic clearance rates and production rates for thyroxine were 21.5 +/- 0.6 ml/kg/day and 1.34 +/- 0.23 micrograms/kg/day, respectively, and T1/2(beta) = 29.6 +/- 2.0 hours. For triiodothyronine, the metabolic clearance rate was 156.6 +/- 12.0 ml/kg/day, the production rate was 0.33 +/- 0.04 micrograms/kg/day, and T1/2 (beta) was 13.3 +/- 1.3 hours. Basel serum thyrotropin levels in five euthyroid animals were 1.4 +/- 0.6 microU/ml and increased after thyrotropin-releasing hormone to 6.7 +/- 2.2 microU/ml. Serum prolactin was 5.8 +/- 0.7 ng/ml, and it increased to 26.6 +/- 4.5 ng/ml after thyrotropin-releasing hormone. Four animals received chronic dexamethasone therapy (1 mg twice daily for 5.5 months). While baseline and thyrotropin-releasing hormone stimulated thyrotropin values were lower (0.8 +/- 0.2 microU/ml and 3.2 +/- 0.5 microU/ml, respectively), these reductions were not significant.