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Single‐ and multiple‐dose pharmacokinetics of oral dolasetron and its active metabolites in healthy volunteers: part 2
Author(s) -
Dimmitt Dan C.,
Choo Youn Sung,
Martin Lorene A.,
Arumugham Thangam,
Hahne William F.,
Weir Scott J.
Publication year - 1999
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/(sici)1099-081x(199901)20:1<41::aid-bdd150>3.0.co;2-g
Subject(s) - pharmacokinetics , pharmacology , active metabolite , medicine , oral dose , oral administration , orally active , metabolite , chemistry
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. Copyright © 1999 John Wiley & Sons, Ltd.