HUMAN DOLASETRON PHARMACOKINETICS .1. DISPOSITION FOLLOWING SINGLE-DOSE INTRAVENOUS ADMINISTRATION TO NORMAL-MALE SUBJECTS

Dolasetron is a 5-hydroxytryptamine antagonist active at type III receptors; it is presently undergoing clinical evaluation for the reduction/prevention of cancer chemotherapy-induced nausea and vomiting. Following intravenous administration to healthy male subjects of doses ranging from 0.6 to 5 mg kg-1, dolasetron disappeared extremely rapidly from plasma; concentrations were generally measurable for only 2-4 h. Less than 1 per cent of the dose was excreted intact in urine. A major plasma metabolite, reduced dolasetron, peaked rapidly at approximately 0.625 h (median). Its median terminal disposition half-life was 7.56 h; median values for fraction of dose excreted in urine and renal clearance were 31.0 per cent and 2.68 ml min-1 kg-1, respectively. Over the dose-range covered, pharmacokinetics of both dolasetron and reduced metabolite appeared to be independent of dose. The median ratio of the areas under the plasma concentration-time curves for metabolite relative to dolasetron was 11.9. As a result of its activity and significant plasma concentrations, reduced dolasetron may play a significant role in pharmacodynamic activity.