Chemical formula: C₂₀H₂₆N₂O₄ Molecular mass: 358.431 g/mol PubChem compound: 3792
Itopride activates the gastrointestinal propulsive motility by antagonistic action on dopamine D2 receptors and inhibitory action on acetylcholine esterase. Itopride activates the release of acetylcholine and inhibits its degradation.
Itopride has also an antiemetic action, based on the interaction with dopamine D2 receptors located in the chemoreceptor area. This effect was demonstrated by the dose dependent inhibition of apomorphineinduced vomiting in dogs.
Itopride accelerates gastric emptying in humans.
It has highly specific action in the upper gastrointestinal tract.
Itopride does not influence plasma concentrations of gastrin.
Itopride is rapidly and almost completely absorbed from the gastrointestinal tract. The relative bioavailability is 60% due to the first-pass effect. Food does not affect the bioavailability. Maximum plasma concentrations (Cmax 0.28 micrograms/ml) are reached 30-45 minutes after administration of 50 mg itopride.
After repeated oral administration of 50-200 mg, 3 times daily, for a period of 7 days, itopride and its metabolites showed linear pharmacokinetics with minimal accumulation.
About 96% of itopride is bound on plasma proteins, mainly albumin. Less than 15% of itopride bound part is bound on alpha-1-acid-glycoprotein.
In rats, itopride is extensively distributed in the tissues (Vdβ = 6.1 l/kg), with the exception of the central nervous system; high concentrations are reached in kidneys, small intestine, liver, adrenal glands and stomach. Protein binding in rats was lower than in humans (78% vs. 96%). The penetration to the central nervous system is minimal. Itopride passes into the milk of lactating rats.
In humans, itopride is extensively metabolized in the liver. Three metabolites have been identified, of which only one manifests minor activity without pharmacological significance (about 2%-3% of itopride effect). Major metabolite in humans is the N-oxide, which is produced by oxidation of the tertiary amine N-di-methyl groups.
Itopride is metabolized by flavine containing monooxygenases (FMO3). The amount and efficacy of human FMO isoenzymes can be associated with genetic polymorphism, which can result in rare autosomal recessive condition known as trimetylaminuria (fish odor syndrome). Biological half-life in patients with trimethylaminuria can be longer.
Pharmacokinetic in vivo studies of CYP-mediated reactions did not prove inhibition or induction of CYP2C19 and CYP2E1 caused by itopride. Administration of itopride did not influence the content of CYP or the activity of uridine-diphosphate-glucuronyl transferase.
Itopride and its metabolites are primarily excreted by urine. The amount of excreted itopride and N-oxide after oral single therapeutic dose to healthy volunteers was 3.7% and 75.4%, respectively.
Itopride elimination half-life is approximately 6 hours.
Preclinical safety studies have been conducted only at high doses overrunning therapeutic human doses and found effect have only little importance for use of itopride in humans. In addition to it humans are less sensitive to hormonal effects observed in animals.
High doses of itopride (30 mg/kg/day) caused hyperprolactinaemia and secondary reversible hyperplasia of uterine mucosa in rats, but not in dogs (dose up to 100 mg/kg/day) or monkeys (dose up to 300 mg/kg/day).
A 3 months toxicity study in dogs has revealed prostate atrophy after oral administration of 30 mg/kg/day dose of itopride. This effect was not induced at 6 months of oral administration of higher doses (100 mg/kg/day) in rats or at higher doses (300 mg/kg/day) in monkeys.
Long-term studies of carcinogenicity in animals have not been carried out.
In series of in vitro and in vivo tests no clastogenic and mutagenic effects of itopride were found.
In fertility studies in female rats with administered doses of 30 mg/kg/day and higher, hyperprolactinaemia and secondary prolongation of oestral cycle after were observed. Prolonged precoital interval was observed at doses 300 mg/kg/day. No side effect on copulation and fertility was proved.
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