Single- and multiple-dose pharmacokinetics of oral dolasetron and its active metabolites in healthy volunteers: part 2

✍ Scribed by Dan C. Dimmitt; Youn Sung Choo; Lorene A. Martin; Thangam Arumugham; William F. Hahne; Scott J. Weir

• Publisher: John Wiley and Sons
• Year: 1999
• Tongue: English
• Weight: 132 KB
• Volume: 20
• Category: Article
• ISSN: 0142-2782
• DOI: 10.1002/(sici)1099-081x(199901)20:1<41::aid-bdd150>3.0.co;2-g

✦ Synopsis

The single-and multiple-dose pharmacokinetics and dose-proportionality of oral dolasetron and its active metabolites over the therapeutic dose range was investigated in 18 healthy men. In an open-label, randomized, complete three-way crossover design, each subject received three separate doses: 50, 100, and 200 mg doses of dolasetron mesylate solution given orally. Each dose was administered on the morning of Days 1 and 3-7 during each of the three treatment periods. Serial blood and urine samples were collected for 48 h after the first and last doses. Blood was analysed for dolasetron and hydrodolasetron concentrations; urine was analysed for dolasetron, the R( + ) and S(-)-enantiomers of hydrodolasetron, and the 5%-hydroxy and 6%-hydroxy metabolites of hydrodolasetron. Dolasetron was rarely detected in plasma. Hydrodolasetron was formed rapidly, with a time to maximum concentration (t max ) of less than 1 h. Steady-state conditions for hydrodolasetron were reached 2 -3 days after starting once-daily dosing. Although statistical significance was found for hydrodolasetron AUC (0 ) and C max between dose groups after both single and multiple doses of dolasetron, the differences were small and unlikely to be of clinical significance. About 17-22% of the dose was excreted in urine as hydrodolasetron, with the majority (\ 83%) as the R(+) enantiomer.