Ganaton Mechanism of Action

Pharmacology: Pharmacokinetics: Absorption: Itopride HCl is rapidly and almost completely absorbed from the gastrointestinal tract. Relative bioavailability is calculated to be 60% due to liver first-pass metabolism. There is no effect of food on bioavailability. Peak plasma levels (C_max=0.28 mcg/mL) are reached after 0.5-0.75 hrs after itopride HCl 50 mg. Following multiple oral doses ranging from 50-200 mg 3 times daily, itopride HCl and its metabolites showed linear pharmacokinetics over a treatment period of 7 days, with minimal accumulation.
Distribution: Approximately 96% of itopride HCl is bound to plasma proteins. Albumin accounts for most of the binding. Alpha₁-acid glycoprotein accounts for <15% of binding.
In rats, itopride is distributed extensively (Vd_β=6.1 L/kg) with high concentrations in the kidneys, small intestines, liver, adrenal glands and stomach. Protein-binding in the rat was lower than that seen in humans (78% vs 96%). The transfer into the central nervous system (CNS), including brain and spinal cord, was minimal. Itopride distributes into the breast milk of rats.
Metabolism: Itopride undergoes extensive hepatic metabolism in humans. Three (3) metabolites have been identified, of which only 1 exerts minor activity without pharmacological relevance (approximately 2-3% of that of itopride). The primary metabolite in humans is the N-oxide, generated by oxidation of the tertiary amine N-dimethyl group.
Itopride is metabolized by a flavin-dependent monooxygenase (FMO3). The abundance and efficiency of the human FMO-isozymes can be subject to genetic polymorphisms, which can lead to a rare autosomal recessive condition known as trimethylaminuria (fish odor syndrome). The half-life (t_½) of itopride may therefore, be longer in trimethylaminuria patients.
In vivo pharmacokinetic studies on CYP-mediated reactions revealed that itopride showed neither inhibitory nor inductory effect on CYP2C19 and CYP2E1. CYP content and uridine diphosphate glucuronosyl transferase activity were not altered with the administration of itopride.
Excretion: Itopride hydrochloride and its metabolites are primarily excreted in the urine. The urinary excretions of itopride and its N-oxide were 3.7% and 75.4%, respectively, in healthy subjects after oral administration of a single therapeutic dose.
The terminal phase t_½ of itopride hydrochloride was approximately 6 hrs.