Pharmacological properties of dolasetron, a potent and selective antagonist at 5‐HT₃ receptors

Abstract

In the rabbit isolated perfused heart, dolasetron (MDL 73,147) was found to be a potent (PA, = 9.8) antagonist at 5-hydroxytryptamine3 (5-HT,) 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,, was approximately 3 p,g/kg and following a dose of 140 p,g/kg iv the reflex was abolished for >85 min.The compound displayed no significant affinity for 5-HT1, 5-HT2, or a variety of other radioligand binding sites at a concentration of 10 FM. 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 mglkg) administered 30 min before and 45 min after 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 behavior of mice were observed at doses up to 100 mg/kg given ip or subcutaneously (sc). It is concluded that dolasetron i s a potent, selective, and reversible antagonist at neuronal 5-HT3 receptors, which i s well tolerated. The compound i s effective at low doses in an animal model predictive of clinical efficacy in cytotoxic drug-induced vomiting. o 1993 Wiley-Liss, Inc.

Transient and long‐lasting actions of 5‐HT on rat dentate gyrus neurones in vitro.

“…Secondly, the lack of voltage dependence and relative insensitivity to the duration of application of 5-HT further supports the hypothesis that a rapid, desensitizing presynaptic excitation is the cause of this transient release of GABA. Finally, the block of this release by dolasetron, a 5-HT3 receptor antagonist (Miller et al 1993), confirms the involvement of this receptor subtype.…”

“…4). The influence of the duration of the pressure application on the duration of the burst was also studied; Giersbergen, Moser & Fozard, 1993) abolished this transient response to the application of 5-HT (n = 6; Fig. 5).…”

Improved prevention of moderately emetogenic chemotherapy‐induced nausea and vomiting with palonosetron, a pharmacologically novel 5‐HT3 receptor antagonist

“…11 The 5-HT 3 receptor binding affinity of palonosetron is approximately 100-fold greater than others in its class, making it more potent than other receptor antagonists (pKi 10.45 for palonosetron vs. 7.6 for dolasetron, 8.39 for ondansetron, and 8.91 for granisetron). 10,13 In addition, the extended plasma elimination half-life of palonosetron (approximately 40 hours) 14 is substantially longer than first-generation agents (dolasetron, 7.5 hours; ondansetron, 4.0 hours; and granisetron, 8.9 hours). [15][16][17] The strong 5-HT 3 receptor binding affinity of palonosetron and prolonged half-life are potential explanations for its prolonged antiemetic activity.…”

Open-label comparison of the antiemetic efficacy of single intravenous doses of dolasetron mesylate in pediatric cancer patients receiving moderately to highly emetogenic chemotherapy

“…Dolasetron mesylate (Anzemet, MDL 73,147EF, Hoechst Marion Roussel) is a new and highly selective 5-HT 3 antagonist [9][10][11] that is rapidly reduced to MDL 74,156, a metabolite with greater activity and a longer half-life than the parent compound [9,12]. In adults, terminal disposition half-life (t 1/2 ) is approximately 7.5 hr with an apparent clearance of 9.3 to 9.5 ml/min/kg (Hoechst Marion Roussel Canada Research).…”