In this first part of a two-part investigation, the intravenous dose proportionality of dolasetron mesylate, a 5-HT3 receptor antagonist, and the absolute bioavailability of oral dolasetron mesylate were investigated. In an open-label, randomized, four-way crossover design, 24 healthy men between the ages of 19 and 45 years received the following doses: 50, 100, or 200 mg dolasetron mesylate administered by 10-min intravenous infusion or 200 mg dolasetron mesylate solution administered orally. Serial blood and urine samples were collected for 48 h after dosing. Following intravenous administration, dolasetron was rapidly eliminated from plasma, with a mean elimination half-life (t(1/2)) of less than 10 min. Dolasetron was rarely detected in plasma after oral administration of the 200 mg dose. Hydrodolasetron, the active primary metabolite of dolasetron, appeared rapidly in plasma following both oral and intravenous administration of dolasetron mesylate, with a mean time to maximum concentration (t(max)) of less than 1 h. The mean t(1/2) of hydrodolasetron ranged from 6.6-8.8 h. The plasma area under the concentration-time curve (AUC((0 --> infinity))) for both dolasetron and hydrodolasetron increased proportionally with dose over the intravenous dose range of 50-200 mg dolasetron mesylate. Approximately 29-33% and 22% of the dose was excreted in urine as hydrodolasetron following intravenous and oral administration of dolasetron, respectively. For dolasetron as well as hydrodolasetron, mean systemic clearance (Cl), volume of distribution (V-d), and t(1/2) were similar at each dolasetron dose. The mean 'apparent' bioavailability of dolasetron calculated using plasma concentrations of hydrodolasetron was 76%. The R( + ) enantiomer of hydrodolasetron represented the majority of drug in plasma (> 75%) and urine ( > 86%). Dolasetron was well tolerated following both oral and intravenous administration Copyright (C) 1999 John Wiley & Sons, Ltd.
