Human dolasetron pharmacokinetics: I. Disposition following single‐dose intravenous administration to normal male subjects

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Abstract
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 0·625h. (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.

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