Human dolasetron pharmacokinetics: I. 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.
Boxenbaum
H
H
Marion Merrell Dow Inc., Kansas City, MO 64134.
Gillespie
T
T
Heck
K
K
Hahne
W
W
D000328:Adult; D006207:Half-Life; D006801:Humans; D007211:Indoles / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D011807:Quinolizines / Q000493:pharmacokinetics*; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D007211:Indoles; D011807:Quinolizines; D012702:Serotonin Antagonists; C060344:dolasetron