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Pharmacological properties of dolasetron, a potent and selective antagonist at 5‐HT 3 receptors
Author(s) -
Miller Robert C.,
Galvan Martin,
Gittos Maurice W.,
van Giersbergen Paul L. M.,
Moser Paul C.,
Fozard John R.
Publication year - 1993
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.430280111
Subject(s) - pharmacology , antagonist , vomiting , chemistry , receptor antagonist , reflex , receptor , medicine , anesthesia
In the rabbit isolated perfused hear, dolasetron (MDL 73,147) was found to be a potent (PA 2 = 9.8) antagonist at 5‐hydroxytryptamine 3 (5‐HT 3 ) receptors present on sympathetic nerve terminals. In anesthetized rats, intravenous (iv), intraduodenal (id), or oral administration of dolasetron blocked the von Bezold‐Jarisch reflex elicited by iv injection of 5‐HT; the iv ED 50 was approximately 3 μg/kg and following a dose of 140 μg/kg iv the reflex was abolished for >85 min. The compound displayed no significant affinity for 5‐HT 1 , 5‐HT 2 , or a variety of other radioligand binding sites at concentration of 10 μM. In conscious ferrets, dolasetron suppressed the vomiting induced by an iv injection of the anti‐cancer drug cisplatin (10 mg/kg). Intravenous doses (0.05–0.5 mg/kg) administered 30 min before and 45 min prior to cisplatin, were clearly anti‐emetic and single oral doses of 0.5 or 2 mg/kg, given 30 min prior to cisplatin were also effective. Minimal changes in the behaviour of mice were observed at doses up to 100 mg/kg given ip or subcutaneously (sc). It is concluded that dolasetron is a potent, selective, and reversible antagonist at neuronal 5‐HT 3 receptors, which is well tolerated. The compound is effective at low doses in an animal model predictive of clinical efficacy in cytotoxic drug‐induced vomiting. © 1993 Wiley‐Liss, Inc.