Description
Granisetron hydrochloride is the second selective 5HT-3-antagonist approved for the
management of nausea and vomiting induced by cancer chemotherapy.Like
ondansetron, granisetron hydrochloride is superior to metoclopramide in both efficacy
and side effect profile. The compound appears to be effective both as a prophylactic
agent and in blocking vomiting once started.
Originator
SmithKline Beecham (United Kingdom)
Manufacturing Process
A solution of 1-(phenylmethyleneamino)isatin (1.354 g, 0.0054 mol) and
endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane (0.832 g, 0.0054 mol) in
dry THF (25 ml) under argon was heated to reflux for 5 hours. The solution
was cooled and evaporated and the residual traces of THF were azeotropically
removed with dichloromethane. The residue was triturated with ether to give
the intermediate 2-(benzylidenehydrazino)-α-oxophenyl-(9-methyl-9-
azabicyclo[3.3.1]non-3-yl)carboxamide as an orange powder (1.583 g, 73%).
Sodium hydride (50 mg, 60% dispersion in oil) was added to a solution of the
2-(benzylidenehydrazino)-α-oxophenyl-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)
carboxamide in dry THF (2.3 ml) under argon at -50°C. The resultant solution
was warmed to 0°C over 20 min then cooled to -30°C and treated with methyl
iodide (0.020 ml). The solution was allowed to warm to room temperature and
stirred for 24 hours then filtered. The filtrate was evaporated to dryness, and
triturated with chloroform to give the 2-(N-methylbenzylidenehydrazo)-α-
oxophenyl-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)carboxamide as a light
coloured powder (50 mg, 38%). Further trituration of the mother liquor gave
a further crop, (37 mg, 28%, after recrystallisation from chloroform).
A solution of 2-(N-methylbenzylidenehydrazo)-α-oxophenyl-(9-methyl-9-
azabicyclo[3.3.1]non-3-yl)carboxamide (37 mg) in methanol (1 ml) was
treated with 2 N hydrochloric acid (0.1 ml) and left at room temperature for
several hours. Evaporation of the solvent gave the crude product as a brown
oil (36 mg). HPLC and MS analysis confirmed the structure and indicated a
quantitative yield of endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-1-
methylindazole-3-carboxamide (Ganisetron).
In practice it is usually used as hydrochloride.
Brand name
Kytril (Roche).
Therapeutic Function
Serotonin antagonist
General Description
Pharmaceutical secondary standards for application in quality control, provide pharma laboratories and manufacturers with a convenient and cost-effective alternative to the preparation of in-house working standards.
Biological Activity
5-HT 3 receptor antagonist that possesses potent antiemetic activity.
Biochem/physiol Actions
Granisetron hydrochloride is a serotonin 5-HT3 receptor antagonist and antiemetic.
Pharmacokinetics
After intravenous injection of 20 or 40 μg/kg of this product in healthy subjects, the average peak plasma concentration was 13.7 and 42.8 μg/L, and the plasma elimination half-life was about 3.1-5.9 hours. Granisetron hydrochloride is widely distributed in the body, the serum protein binding rate is about 65%, and most of it is rapidly metabolized. The main metabolic pathway is N-dealkylation and aromatic epoxidation and then conjugated. It is excreted in feces and urine.
Pharmacology
Granisetron Hydrochloride is a highly selective 5-HT3 receptor antagonist with good preventive and therapeutic effects on nausea and vomiting caused by radiotherapy, chemotherapy and surgery. Factors such as radiotherapy, chemotherapy and surgery can cause enterochromaffin cells to release 5-HT, and 5-HT can activate 5-HT3 receptors in the central or vagus nerve and cause gag reflex. The mechanism of this product to control nausea and vomiting is to inhibit the occurrence of nausea and vomiting by antagonizing the 5-HT3 receptors in the central chemoreceptor area and peripheral vagus nerve endings.
Veterinary Drugs and Treatments
Granisetron is an alternative to other 5-HT3 receptor antagonists
(e.g., ondansetron or dolasetron) for the treatment of severe vomiting
or prophylaxis before administering antineoplastic drugs such
as cisplatin that can cause severe vomiting.
storage
Desiccate at +4°C
References
[1] Patent: WO2008/151677, 2008, A1. Location in patent: Page/Page column 13
[2] Patent: US2010/48613, 2010, A1. Location in patent: Page/Page column 2
