Kytril Mechanism of Action

Antiemetics, Serotonin (5HT₃) antagonists.
Pharmacology: Pharmacodynamics: Mechanism of Action: Serotonin receptors of the 5-HT₃ type are located peripherally in vagal nerve terminals and centrally in the chemoreceptor trigger zone of the area postrema. During chemotherapy-induced vomiting, mucosal enterochromaffin cells release serotonin, which stimulates 5-HT₃ receptors. This invokes vagal afferent discharge, inducing vomiting.
Kytril is a potent anti-emetic and highly selective antagonist of 5-hydroxytryptamine (5-HT₃) receptors. Radioligand binding studies have demonstrated that Kytril has negligible affinity for other receptor types including 5-HT and dopamine D₂ binding sites.
Efficacy/Clinical Studies: Chemotherapy-induced nausea and vomiting (CINV): KYTRIL administered intravenously has been shown to be effective in the prevention and treatment of nausea and vomiting associated with cancer chemotherapy in adults. Kytril administered orally has been shown to be effective in the prevention of nausea and vomiting associated with cancer chemotherapy. Kytril administered intravenously has been shown to be effective in children aged 2 years and above for the prevention and treatment of acute CINV. There is insufficient information to recommend the oral administration of KYTRIL in the prevention and treatment of CINV in pediatric patients.
Radiation-induced nausea and vomiting (RINV): Kytril administered orally has been shown to be effective in the prevention and treatment of nausea and vomiting associated with total body or fractionated abdominal irradiation in adults. Efficacy in children has not been established in controlled clinical trials.
Postoperative nausea and vomiting (PONV): Kytril administered intravenously has been shown to be effective for prevention and treatment of post-operative nausea and vomiting in adults.
Pharmacokinetics: Absorption: Absorption of Kytril is rapid and complete, though oral bioavailability is reduced to about 60% as a result of first pass metabolism. Oral bioavailability is generally not influenced by food.
Distribution: Kytril is extensively distributed, with a mean volume of distribution of approximately 3l/kg. Plasma protein binding is approximately 65%.
Metabolism: Biotransformation pathways involve N-demethylation and aromatic ring oxidation followed by conjugation. In-vitro liver microsomal studies show that granisetron's major route of metabolism is inhibited by ketoconazole, suggestive of metabolism mediated by the cytochrome P-450 3A subfamily.
Elimination: Clearance is predominantly by hepatic metabolism. Urinary excretion of unchanged Kytril averages 12% of dose while that of metabolites amounts to about 47% of dose. The remainder is excreted in feces as metabolites. Mean plasma half-life in patients by the oral and intravenous route is approximately 9 hours, with a wide inter-subject variability.
The pharmacokinetics of oral and intravenous Kytril demonstrate no marked deviations from linear pharmacokinetics at oral doses up to 2.5-fold and intravenous doses up to 4-fold the recommended clinical dose.
The results of a study in healthy male volunteers have demonstrated that systemic delivery of 3 mg granisetron from an intramuscular injection is slower than from a 5 minute intravenous infusion (as indicated by lower Cmax and later Tmax). In other respects, the pharmacokinetics of granisetron are virtually indistinguishable when administered by these two different routes.
Pharmacokinetics in Special Populations: Renal failure: In patients with severe renal failure, data indicate that pharmacokinetic parameters after a single intravenous dose are generally similar to those in normal subjects.
Hepatic impairment: In patients with hepatic impairment due to neoplastic liver involvement, total plasma clearance of an intravenous dose was approximately halved compared to patients without hepatic involvement. Despite these changes, no dosage adjustment is necessary.
Elderly: In elderly subjects after single intravenous doses, pharmacokinetic parameters were within the range found for non-elderly subjects.
Pediatrics: In children, after single intravenous doses, pharmacokinetics are similar to those in adults when appropriate parameters (volume of distribution, total plasma clearance) are normalized for body weight.
Toxicology: Preclinical Safety: Preclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, reproductive toxicity and genotoxicity. Carcinogenicity studies revealed no special hazard for humans when used in the recommended human dose. However, when administered in higher doses and over a prolonged period of time the risk of carcinogenicity cannot be ruled out.
In carcinogenicity studies in rats and mice treated orally for their lifetime (2 years), no adverse findings were observed at dosages 25 times the clinical dose. At higher doses, KYTRIL induced cell proliferation in the rat liver and hepatocellular tumors in rats and mice.
KYTRIL was not mutagenic in mammalian or non-mammalian in vivo or in vitro test systems and there was no evidence of unscheduled DNA synthesis indicating that KYTRIL is not genotoxic.
In the rat, KYTRIL had no untoward effect on reproductive performance, fertility or on pre- and post natal development.
Teratogenic effects were not observed in rats or rabbits.