Source: Health Products Regulatory Authority (ZA) Revision Year: 2022 Publisher: Acino Pharma (Pty) Ltd, 106 16th Road, Midrand, 1686
Category and Class: A 5.7.2 Anti-emetics and anti-vertigo preparations
Pharmacotherapeutic group: Antiemetics and antinauseants, serotonin (5HT3) antagonists
ATC code: A04AA02
Granisetron is a selective antagonist of 5-hydroxytryptamine (5-HT)3 receptors with antiemetic properties. Radioligand binding studies have demonstrated that granisetron has negligible affinity for other receptor types including other 5-HT and dopamine D2 binding sites.
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, which triggers a response from the vagal afferent receptors and the emetic centre is then stimulated, inducing vomiting.
Granisetron is absorbed after oral administration, with peak plasma concentrations occurring 2 hours after dosing. Due to first-pass metabolism, the oral bioavailability of granisetron is about 60%.
Oral bioavailability is generally not influenced by food.
Granisetron is extensively distributed, with a mean volume of distribution of about 3 l/kg. Plasma protein binding is approximately 65%.
Granisetron is metabolised primarily by 7-hydroxylation.
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.
The pharmacokinetics of granisetron exhibit considerable inter-individual variation. The elimination half-life is reported to be approximately 3 to 4 hours in healthy individuals and about 9 to 12 hours in cancer patients.
Mean plasma half-life (t½) in patients is approximately 9 hours, with a wide inter-individual variability.
Granisetron clearance is not affected by renal impairment, but is lower in the elderly and in patients with hepatic impairment.
Clearance is predominantly by hepatic metabolism. Urinary excretion of unchanged granisetron averages 12% of dose while that of metabolites amounts to about 47% of the dose.
The remainder is excreted in faeces as metabolites.
The pharmacokinetics of granisetron demonstrate no marked deviations from linear pharmacokinetics at oral doses up to 2,5-fold the recommended clinical dose.
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