Comparison of the Pharmacokinetics of Dolasetron and Its Major Active Metabolite, Reduced Dolasetron, in Dog

Dolasetron mesilate (Anzemet) ((2α,6α,8α,9aβ-octahydro-3-oxo-2,6-methano-2H-quinolizin-8-yl-1H-indole-3-carboxylate monomethane- sulfonate) is a 5-HT3 receptor antagonist, which is in development for the treatment of chemotherapy-induced emesis. The ketone moiety of dolasetron is rapidly reduced by carbonyl reductase to form an alcohol, reduced dolasetron (red-dolasetron), which is the major pharmacologically active metabolite in humans. The pharmacokinetics of dolasetron and red-dolasetron were compared in dog, after single intravenous (iv) (2mg/kg) and oral (po) (5mg/kg) administration of [14C]dolasetron or [14C]-red-dolasetron. Pharmacokinetic parameters of dolasetron showed a terminal elimination half-life (t1/2) of 0.1 h, total body plasma clearance (Cltot) of around 109mL/min/kg, apparent volume of distribution (aVdβ) of 0.83 L/kg, and bioavailability (F) of 7%. Pharmacokinetic parameters of red-dolasetron, calculated after dolasetron or red-dolasetron administration, were very similar. The t1/2 was around 4.0 h, Cltot 25mL/min/kg, aVdβ 8.5 L/kg, and F around 100%. The apparent first-order formation rate constant (kf) of red-dolasetron was 7h−1, which was similar to the first-order elimination rate constant (kel) of dolasetron. Cmax of red-dolasetron was similar, after po administration of either compound, but the median Tmax was 0.33h after dolasetron, compared with 1.5h after red-dolasetron. The first-order absorption rate constants (ka) of dolasetron and red-dolasetron were 14h−1 and 2h−1, respectively. Dolasetron transport across Caco-2 cell monolayers was also higher than that of red-dolasetron. Thus dolasetron was more quickly absorbed than red-dolasetron, and its administration led to the more rapid appearance of red-dolasetron in plasma. There appears to be no advantage in the direct administration of the metabolite, especially as in humans oral administration of dolasetron, 30min before chemotherapy, has been shown to be effective in preventing emesis.