PHARMACOKINETICS OF DOLASETRON FOLLOWING SINGLE-DOSE AND MULTIPLE-DOSE INTRAVENOUS ADMINISTRATION TO NORMAL-MALE SUBJECTS

Dolasetron, Anzemet(TM), a 5-hydroxytryptamine receptor antagonist, is under investigation as an antiemetic agent. The keto-reduced metaboli te of dolasetron has been identified in human plasma and is probably r esponsible for the majority of the antiemetic activity. This study eva luated the pharmacokinetics of dolasetron and the reduced metabolite f ollowing single and multiple intravenous (IV) infusions of dolasetron mesylate in healthy male subjects. Four groups of subjects (six active /two placebo) received either dolasetron mesylate or placebo in single IV doses ranging from 0.30 to 0.60 mg kg(-1) on day 1 and multiple IV doses ranging from 0.60 to 1.20 mg kg(-1) d(-1) on days 2-9. Dolasetr on could be detected for less than Ih, while the reduced metabolite ap peared rapidly in the plasma, reaching a maximal plasma concentration in less than 1 h. Reduced metabolite maximal plasma concentration was proportional to the dose and the area under plasma concentration curve was linear based on regression analysis. The half-life of reduced met abolite ranged from 3.82 to 7.46 h. The mean renal clearance of reduce d metabolite was 2.20-4.43 mL min(-1) kg(-1) and was dose independent. All of the evidence supports dose independent pharmacokinetics for th e reduced metabolite. Upon multiple dosing, the reduced metabolite AUC can be predicted from the single-dose pharmacokinetics of this metabo lite.