Evaluation of the Pharmacokinetics and Tolerance of Allopurinol Riboside in Human Volunteers

摘要

Allopurinol riboside is an experimental drug, of potential use in the treatment of leishmaniasis and Chagas' disease. A Phase I study of multiple doses of allopurinol riboside, to evaluate safety and pharmacokinetics, was conducted in 18 healthy male volunteers. Seven dosage levels were tested: 250, 500, 750, 1000, 1250, 1500 and 1750 mg, given on a gid schedule (1000-7000 mg/day) for a total of 13 doses. Two volunteers were evaluated at each level. Four additional volunteers received 1500 mg qid for 25 doses, over a period of 7 days. The study was conducted in three phases: screening, a five- or eight-day in-hospital phase, and a two-week follow-up phase. Safety monitoring included serial clinical evaluations, blood tests, electrocardiograms and urinalyses. Plasma an during samples were collected for drug and metabolite determination by high pressure liquid chromatography. Allopurinol riboside was safe and well-tolerated by the volunteers in this study, in doses up to 7 grams/day for three days, or 6 grams/day for six days. Steady state plasma levels of allopurinol riboside with troughs exceeding 2 microgram/ml are achievable. The metabolites, oxipurinol and allopurinol, appear in plasma and urine, in a dose-dependent fashion, but at the doses studied did not give rise to crystalluria or other signs of toxicity.