Granisetron - How It Works
Clinical pharmacology details from the US FDA-approved label: how Granisetron works in your body, how it's absorbed, how long it stays active, and how it's eliminated.
CLINICAL PHARMACOLOGY Granisetron is a selective 5-hydroxytryptamine 3 (5-HT 3 ) receptor antagonist with little or no affinity for other serotonin receptors, including 5-HT 1 ; 5-HT 1A ; 5-HT 1B/C ; 5-HT 2 ; for alpha 1 -, alpha 2 -, or beta-adrenoreceptors; for dopamine-D 2 ; or for histamine-H 1 ; benzodiazepine; picrotoxin or opioid receptors.
Serotonin receptors of the 5-HT 3 type are located peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone of the area postrema.
During chemotherapy that induces vomiting, mucosal enterochromaffin cells release serotonin, which stimulates 5-HT 3 receptors.
This evokes vagal afferent discharge, inducing vomiting.
Animal studies demonstrate that, in binding to 5-HT 3 receptors, granisetron blocks serotonin stimulation and subsequent vomiting after emetogenic stimuli such as cisplatin.
In the ferret animal model, a single granisetron injection prevented vomiting due to high-dose cisplatin or arrested vomiting within 5 to 30 seconds.
In most human studies, granisetron has had little effect on blood pressure, heart rate or ECG.
No evidence of an effect on plasma prolactin or aldosterone concentrations has been found in other studies.
Following single and multiple oral doses, Kytril tablets slowed colonic transit in normal volunteers.
However, granisetron had no effect on oro-cecal transit time in normal volunteers when given as a single intravenous (IV) infusion of 50 mcg/kg or 200 mcg/kg.
Pharmacokinetics In healthy volunteers and adult cancer patients undergoing chemotherapy, administration of Kytril tablets produced mean pharmacokinetic data shown in Table 1 .
Table 1 Pharmacokinetic Parameters (Median [range]) Following Kytril Tablets 1 Not determined after oral administration; following a single intravenous dose of 40 mcg/kg, terminal phase half-life was determined to be 8.95 hours.
Peak Plasma Concentration (ng/mL) Terminal Phase Half-Life (h) Volume of Distribution (L/kg) Total Clearance (L/h/kg) Cancer Patients 1 mg bid, 7 days (n=27) 5.99 [0.63 to 30.9] N.D.
0.52 [0.09 to 7.37] Volunteers Single 1 mg dose (n=39) 3.63 [0.27 to 9.14] 6.23 [0.96 to 19.9] 3.94 [1.89 to 39.4] 0.41 [0.11 to 24.6] A 2 mg dose of GRANISOL oral solution is bioequivalent to the corresponding dose of Kytril tablets (1 mg x 2) and may be used interchangeably.
Absorption When Kytril tablets were administered with food, AUC was decreased by 5% and C max increased by 30% in non-fasted healthy volunteers who received a single dose of 10 mg.
Distribution Plasma protein binding is approximately 65% and granisetron distributes freely between plasma and red blood cells.
Metabolism Granisetron metabolism involves 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.
Animal studies suggest that some of the metabolites may also have 5-HT 3 receptor antagonist activity.
Elimination Clearance is predominantly by hepatic metabolism.
Pharmacokinetics
Pharmacokinetics In healthy volunteers and adult cancer patients undergoing chemotherapy, administration of Kytril tablets produced mean pharmacokinetic data shown in Table 1 . Table 1 Pharmacokinetic Parameters (Median [range]) Following Kytril Tablets 1 Not determined after oral administration; following a single intravenous dose of 40 mcg/kg, terminal phase half-life was determined to be 8.95 hours. N.D. Not determined. Peak Plasma Concentration (ng/mL) Terminal Phase Half-Life (h) Volume of Distribution (L/kg) Total Clearance (L/h/kg) Cancer Patients 1 mg bid, 7 days (n=27) 5.99 [0.63 to 30.9] N.D. 1 N.D. 0.52 [0.09 to 7.37] Volunteers Single 1 mg dose (n=39) 3.63 [0.27 to 9.14] 6.23 [0.96 to 19.9] 3.94 [1.89 to 39.4] 0.41 [0.11 to 24.6] A 2 mg dose of GRANISOL oral solution is bioequivalent to the corresponding dose of Kytril tablets (1 mg x 2) and may be used interchangeably. Absorption When Kytril tablets were administered with food, AUC was decreased by 5% and C max increased by 30% in non-fasted healthy volunteers who received a single dose of 10 mg. Distribution Plasma protein binding is approximately 65% and granisetron distributes freely between plasma and red blood cells. Metabolism Granisetron metabolism involves 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