PHARMACOLOGY OF THE HUMAN METABOLITES OF DOLASETRON, AN ANTIEMETIC 5-HT3 RECEPTOR ANTAGONIST

Dolasetron mesylate (MDL 73,147EF) is a novel 5-HT3 receptor antagonist under development as an anti-emetic. Dolasetron undergoes rapid and extensive metabolism to form a major metabolite, MDL 74,156; the metabolism is stereoselective, with the [+]-enantiomer (MDL 73,405) predominant. MDL 74,156 is also hydroxylated to form MDL 102, 382 (5'-OH metabolite) and MDL 73,492 (6'-OH metabolite). The present study evaluated the pharmacological properties of dolasetron and its human metabolites in vitro and following oral and intravenous administration in rats and compared the antiemetic effects of dolasetron and ondansetron in dogs. Each of the metabolites had high affinity at and was selective for 5-HT, receptors. In anesthetized rats, the 5-HT-mediated von Bezold-Jarisch reflex was inhibited by 1 mg/kg oral doses of either dolasetron (3.1 mu mol/kg), ondansetron (3.4 mu mol/kg), granisetron (3.2 mu mol/kg), or tropisetron (3.5 mu mol/kg) and by intravenous doses of dolasetron and ondansetron. Dolasetron had a significantly longer duration of action than ondansetron. In addition, the metabolites MDL 73,405, MDL 102,382, and MDL 73,492 exhibited significant 5-HT, receptor antagonist activity following intravenous administration, but only MDL 73,405 exhibited significant activity following oral administration. Both dolasetron mesylate and ondansetron reduced the number of emetic episodes and increased the ti me to first emetic event in cisplatin-treated dogs. The clinical effects and duration of action observed following administration of dolasetron mesylate to humans are likely due mainly to MDL 73,405 (the [+]-enantiomer of MDL 74,156). (C) 1995 Wiley-Liss, Inc.