Palonosetron

Palonosetron is a 5-HT3 receptor antagonist. It binds strongly to this receptor and has little or no affinity for other receptors. Chemotherapy drugs are thought to cause nausea and vomiting by releasing serotonin from the enterochromaffin cells of the small intestine. The released serotonin then activates 5-HT3 receptors on the nerve terminals of the vagus in the periphery, and also centrally in the chemoreceptor trigger zone of the area postrema, which starts the vomiting reflex. Postoperative nausea and vomiting is influenced by many patient, surgical and anesthesia related factors. It is triggered by the release of 5-HT3 in a cascade of neuronal events involving both the central nervous system and the gastrointestinal tract. The 5-HT3 receptor has been shown to take part selectively in the emetic response. Palonosetron works by blocking the actions of serotonin, which is linked with nausea and vomiting, at the 5-HTs receptor. It most likely acts in the small intestine, though it may also act in the brain.

Pharmacokinetics: Palonosetron shows linear, dose-proportional pharmacokinetics over the dose range 1-90 pg/kg in healthy subjects and in cancer patients. In cancer patients given single intravenous doses in this range, the mean maximum plasma concentration (Cmax) ranges from 0.89 to 336 ng/ml. The area under the plasma concentration-time curve from zero to infinity (AUCo-co) ranges from 13.8 to 957 ng.h/ml. The volume of distribution is approximately 6.9-7.9 L/kg, and approximately 62% of the drug is bound to plasma proteins. Approximately 50% of Palonosetron is metabolized into two inactive metabolites, each showing <1% of the 5-HT3 receptor antagonist activity. Approximately 40% of the drug is metabolised via the kidney, and 50% by the liver, mainly through the CYP2D6 isoenzyme, with CYP3A4 and CYP1A2 also involved. About 50% of the drug goes through metabolism. After a single intravenous dose, approximately 40% is excreted unchanged in the urine after 144 hours. In healthy subjects, total body clearance is 160±35 ml/h/kg and renal clearance is 66.5±18.2 ml/h/kg. Palonosetron has a longer half-life (40 hours) and a greater 5-HT3 receptor binding affinity.