Pharmacology of the human metabolites of dolasetron, an antiemetic 5‐HT₃ receptor antagonist

Abstract

Dolasetron mesylate (MDL 73,147EF) i s 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 [ + 1-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-HT3 receptors. In anesthetized rats, the 5-HT-mediated von Bezold-Jarisch reflex was inhibited by 1 mglkg oral doses of either dolasetron (3.1 pmol/kg), ondansetron (3.4 bmol/kg), granisetron (3.2 pmol/kg), or tropisetron (3.5 pmol/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-HT3 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 time 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 [ t 1-enantiomer of MDL 74,156). o 1995 Wiley-Liss, Inc.

Intravenous pharmacokinetics and absolute oral bioavailability of dolasetron in healthy volunteers: part 1

“…This is a key finding. The relative antagonist properties of dolasetron and R(+), S(− ), 5%OH, and 6%OH-hydrodolasetron to 5-HT 3 receptors were evaluated by characterizing the in vitro receptor binding affinities of these compounds to 5-HT 3 binding sites using NG108-15 neuroblastoma×glioma cell membrane preparations [18]. All showed high affinity for 5-HT 3 binding Table 5.…”

“…For the intravenous doses, blood samples were collected immediately before the start of the infusion, and at 0, 0.083 (5 min), 0.25, 0.5, 0.75, 1,2,4,6,8,12,18,24,36, and 48 h post-infusion. For the oral dose, blood samples were collected immediately before the dose, and at 0.25, 0.5, 0.75, 1,2,4,6,8,12,18,24,36, and 48 h after the dose.…”

“…For the oral dose, blood samples were collected immediately before the dose, and at 0.25, 0.5, 0.75, 1,2,4,6,8,12,18,24,36, and 48 h after the dose. Each 9.5 mL sample of blood was collected into prechilled, EDTA-containing Venoject tubes, then gently mixed.…”

A double-blind, placebo-controlled trial of i.v. dolasetron mesilate in the prevention of radiotherapy-induced nausea and vomiting in cancer patients

“…Dolasetron mesilate, previously referred to as MDL 73,147EF, is a 5-HT3 receptor antagonist with high potency and selectivity both in vivo and in vitro [10]. Dolasetron and its reduced metabolite, MDL 74,156, have been shown to prevent cisplatin-induced vomiting in ferrets [10] and dogs [3], and in clinical trials have ameliorated the nausea and vomiting in patients receiving cisplatin [2-5, 8, 9, 11].…”

Lack of Effect of Aprepitant on Hydrodolasetron Pharmacokinetics in CYP2D6 Extensive and Poor Metabolizers

“…Dolasetron is a prodrug that is rapidly converted to hydrodolasetron, which is believed to be responsible for the majority of clinical activity 8–11 . Hydrodolasetron is metabolized largely via cytochrome P450 (CYP) D6 12 .…”