Pharmacology: Pharmacodynamics: Rabeprazole: Rabeprazole belongs to a class of antisecretory compounds (substituted benzimidazole proton-pump inhibitors) that do not exhibit anticholinergic or histamine H2-receptor antagonist properties, but suppress gastric acid secretion by inhibiting the gastric H+, K+ATPase at the secretory surface of the gastric parietal cell. Because this enzyme is regarded as the acid (proton) pump within the parietal cell, rabeprazole has been characterized as a gastric proton-pump inhibitor. Rabeprazole blocks the final step of gastric acid secretion. In gastric parietal cells, rabeprazole is protonated, accumulates, and is transformed to an active sulfenamide. When studied in vitro, rabeprazole is chemically activated at pH 1.2 with a half-life of 78 seconds. It inhibits acid transport in porcine gastric vesicles with a half-life of 90 seconds.
Antisecretory Activity: The antisecretory effect begins within one hour after oral administration of 20 mg rabeprazole. The median inhibitory effect of rabeprazole on 24 hour gastric acidity is 88% of maximal after the first dose. Rabeprazole 20 mg inhibits basal and peptone meal-stimulated acid secretion versus placebo by 86% and 95%, respectively, and increases the percent of a 24-hour period that the gastric pH>3 from 10% to 65%. This relatively prolonged pharmacodynamic action compared to the short pharmacokinetic half-life (1-2 hours) reflects the sustained inactivation of the H+, K+ATPase.
Effects on Esophageal Acid Exposure: In patients with gastroesophageal reflux disease (GERD) and moderate to severe esophageal acid exposure, Rabeprazole 20 mg and 40 mg per day decreased 24-hour esophageal acid exposure.
Effects on Serum Gastrin: In patients given daily doses of rabeprazole for up to eight weeks to treat ulcerative or erosive esophagitis and in patients treated for up to 52 weeks to prevent recurrence of disease the median fasting gastrin level increased in a dose-related manner. The group median values stayed within the normal range.
Effects on Enterochromaffin-like (ECL) Cells: Increased serum gastrin secondary to antisecretory agents stimulates proliferation of gastric ECL cells which, over time, may result in ECL cell hyperplasia in rats and mice and gastric carcinoids in rats, especially in females.
Endocrine Effects: Studies in humans for up to one year have not revealed clinically significant effects on the endocrine system.
Other Effects: In humans treated with rabeprazole for up to one year, no systemic effects have been observed on the central nervous, lymphoid, hematopoietic, renal, hepatic, cardiovascular, or respiratory systems. No data are available on long term treatment with rabeprazole and ocular effects.
Itopride: ltopride promotes gastrointestinal motility through synergism of its dopamine D 2-receptor antagonistic action and its acetylcholine esterase inhibitory action. In addition to these actions, Itopride has an antiemetic action, which is based on its dopamine D2 receptor antagonistic action at CTZ.
Pharmacokinetics: Rabeprazole: Rabeprazole Sodium + Itopride Hydrochloride capsules are enteric coated to allow Rabeprazole sodium, which is acid labile to pass through the stomach relatively. After oral administration of 20 mg rabeprazole, peak plasma concentrations (Cmax) of rabeprazole occur over a range of 2.0 to 5.0 hours (Tmax). The rabeprazole Cmax and AUC are linear over an oral dose range of 10 mg to 40 mg. There is no appreciable accumulation when doses of 10 mg to 40 mg are administered every 24 hours; the pharmacokinetics of rabeprazole is not altered by multiple dosing. The plasma half-life ranges from 1 to 2 hours.
Absorption: Absolute bioavailability for a 20 mg oral tablet of rabeprazole (compared to intravenous administration) is approximately 52%. Rabeprazole may be taken without regard to timing of meals.
Distribution: Rabeprazole is 96.3% bound to human plasma proteins.
Metabolism: Rabeprazole is extensively metabolized. The thioether and sulphone are the primary metabolites measured in human plasma. In vitro studies have demonstrated that rabeprazole is metabolized in the liver primarily by cytochromes P450 3A (CYP3A) to a sulphone metabolite and cytochrome P450 2C19 (CYP2C19) to desmethyl rabeprazole. The thioether metabolite is formed non-enzymatically by reduction of rabeprazole.
Excretion: Following a single 20 mg oral dose of 14 C-labeled rabeprazole, approximately 90% of the drug was eliminated in the urine, primarily as thioether carboxylic acid; its glucuronide, and mercapturic acid metabolites. The remainder of the dose was recovered in the feces. No unchanged rabeprazole was recovered in the urine or feces.
Itopride: Absorption: On oral administration, Itopride is rapidly and extensively absorbed and peak serum concentrations are achieved within 35 minutes after oral dosing. Food does not affect its absorption.
Metabolism: Itopride is metabolized in the liver by N-oxidation to inactive metabolites by the enzyme flavin-containing monooxygenase (FMO). Biotransformation of itopride does not involve the cytochrome P450 enzyme system, thus, it is devoid of drug interaction potential with cytochrome P450 enzyme inhibitors.
Excretion: The half-life of Itopride is about 6 hours. It is excreted mainly by the kidneys as metabolites and unchanged drug. Food did not significantly affect the absorption of Itopride.