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

✍ Scribed by Harold Boxenbaum; Todd Gillespie; Kathleen Heck; William Hahne

• Publisher: John Wiley and Sons
• Year: 1992
• Tongue: English
• Weight: 471 KB
• Volume: 13
• Category: Article
• ISSN: 0142-2782
• DOI: 10.1002/bdd.2510130907

✦ Synopsis

Dolasetron is a 5-hydroxytryptamine antagonist active at type 111 receptors; it is presently undergoing clinical evaluation for the reduction/prevention of cancer chemotherapyinduced nausea and vomiting. Following intravenous administration to healthy male subjects of doses ranging from 0.6 to 5 mg kg-I, 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-' kg-I, 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.