PROGIT Film-coated tablet Ref.[11050] Active ingredients: Itopride

Absorption

Itopride is absorbed rapidly and almost completely from gastrointestinal tract. Relative bioavailability about 60% is due to first-pass effect. Food does not affect bioavailability of the product. Maximum plasma concentrations are reached in 30 to 50 minutes after administration of 50 mg of itopride.

After repeated administration of doses in the range of 50 to 200 mg 3 times a day for period of 7 days, itopride and its metabolites have shown pharmacokinetics of linear type with minimal accumulation.

Distribution

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 distributed extensively in the tissues (Vd_β = 6.1 l/kg) except for 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% contrary to 96%). Penetration into the central nervous system was minimal. Itopride is excreted in milk of lactating rats.

Biotransformation

Itopride is extensively metabolised in liver in humans. Three metabolites were identified of which only one manifests minor activity without pharmacological significance (about 2 to 3% of itopride effect). Itopride is metabolised by flavine monoxygenase (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 trimethylaminuria (fish odour 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 CYP2C19 and CYP2E1 caused by itopride. Administration of itopride did not influence content of CYP or the activity of uridine-diphosphate-glucuronyl transferase.

Elimination

Itopride and its metabolites are primarily excreted by urine. The amount of excreted itopride and Noxide after oral single therapeutic dose to healthy volunteers was 3.7% and 75.4%, respectively. Half-life of itopride is about 6 hours.

Oral single lethal dose was 2,000 mg/kg in mice and rats and approximately 600 mg/kg in dogs. Preclinical safety studies were carried out only with doses multiplicatively 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. Nevertheless this was not proved in dogs (dose up to 100 mg/kg/day) and monkeys (dose up to 300 mg/kg/day). 3-month toxicity study in dogs has revealed prostate atrophy after oral administration in dose 30 mg/kg/day. This effect was induced neither after 6-month administration of higher doses (100 mg/kg/day) in rats nor more higher doses (300 mg/kg/day) in monkeys.

Long-term studies of cancerogenity 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 who were administered doses 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.