The initial step in the metabolism of dolasetron or MDL 73,147EF [(2 alpha, 6 alpha, 8 alpha, 9a beta)-octahydro-3-oxo-2,6-methano-2H- quinolizin-8-yl 1H-indol-3-carboxylate, monomethanesulfonate] is the reduction of the prochiral carbonyl group to give a chiral secondary alcohol "reduced dolasetron." An HPLC method, using a chiral column to separate reduced dolasetron enantiomers, has been developed and used to measure enantiomers in urine of rats, dogs, and humans after dolasetron administration. In all cases, the reduction was enantioselective for the (+)-(R)-enantiomer, although the dog showed lower stereoselectivity, especially after iv administration. An approximate enantiomeric ratio (+/-) of 90:10 was found in rat and human urine. The contribution of further metabolism to this enantiomeric ratio was considered small as preliminary studies showed that oxidation of the enantiomeric alcohols by human liver microsomes demonstrated only minor stereoselectivity. Further evidence for the role of stereoselective reduction in man was obtained from in vitro studies, where dolasetron was incubated with human whole blood. The enantiomeric composition of reduced dolasetron formed in human whole blood was the same as that found in human urine after administration of dolasetron. Enantioselectivity was not due to differences in the absorption, distribution, metabolism, or excretion of enantiomers, as iv or oral administration of rac-reduced dolasetron to rats and dogs lead to the recovery, in urine, of essentially the same enantiomeric composition as the dose administered. it is fortuitous that the (+)-(R)-enantiomer is predominantly formed by carbonyl reductase, as it is the more active compound.

Dolasetron mesilate (Anzemet) ((2 alpha, 6 alpha, 8 alpha, 9a beta)-octahydro-3-oxo-2,6-methano-2H-quinolizin-8-yl-1 H-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 (i.v.) (2 mg/kg) and oral (p.o.) (5 mg/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 109 mL/min/kg, apparent volume of distribution (aVd beta) 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 25 mL/min/kg, aVd beta 8.5 L/kg, and F around 100%. The apparent first-order formation rate constant (ki) of red-dolasetron was 7 h-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 0.33 h after dolasetron, compared with 1.5 h after red-dolasetron. The first-order absorption rate constants (ka) of dolasetron and red-dolasetron were 14 h-1 and 2 h-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, 30 min before chemotherapy, has been shown to be effective in preventing emesis.

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