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

Dolasetron mesylate (MDL 73,147EF) is a novel 5-HT3 receptor antagonis t under development as an anti-emetic. Dolasetron undergoes rapid and extensive metabolism to form a major metabolite, MDL 74,156; the metab olism is stereoselective, with the [+]-enantiomer (MDL 73,405) predomi nant. MDL 74,156 is also hydroxylated to form MDL 102, 382 (5'-OH meta bolite) and MDL 73,492 (6'-OH metabolite). The present study evaluated the pharmacological properties of dolasetron and its human metabolite s in vitro and following oral and intravenous administration in rats a nd compared the antiemetic effects of dolasetron and ondansetron in do gs. Each of the metabolites had high affinity at and was selective for 5-HT, receptors. In anesthetized rats, the 5-HT-mediated von Bezold-J arisch 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 dolas etron and ondansetron. Dolasetron had a significantly longer duration of action than ondansetron. In addition, the metabolites MDL 73,405, M DL 102,382, and MDL 73,492 exhibited significant 5-HT, receptor antago nist activity following intravenous administration, but only MDL 73,40 5 exhibited significant activity following oral administration. Both d olasetron mesylate and ondansetron reduced the number of emetic episod es and increased the ti me to first emetic event in cisplatin-treated dogs. The clinical effects and duration of action observed following a dministration of dolasetron mesylate to humans are likely due mainly t o MDL 73,405 (the [+]-enantiomer of MDL 74,156). (C) 1995 Wiley-Liss, Inc.