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Pharmacology: Pharmacodynamics: Mechanism of Action: Rabeprazole Sodium belongs to the class of antisecretory compounds, the substituted benzimidazoles, that do not exhibit anticholinergic or H2 histamine antagonist properties, but suppress gastric acid secretion by the specific inhibition of the H+/K+- ATPase enzyme at the secretory surface of the gastric parietal cell. This enzyme system is regarded as the acid (proton) pump, and therefore Rabeprazole Sodium is classified as a gastric proton-pump inhibitor (PPI) blocking the final step of acid production. This effect is dose-related and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus.
Anti-secretory Activity: After oral administration of a 20 mg dose of Rabeprazole Sodium the onset of the anti-secretory effect occurs within one hour with the maximum effect occurring within two to four hours. Inhibition of basal and food stimulated acid secretion 23 hours after the first dose of Rabeprazole Sodium are 69% and 82% respectively and the duration of inhibition lasts up to 48 hours. This duration of pharmacodynamic action is much longer than the pharmacokinetic half-life (approximately one hour) would predict. This effect is probably due to the prolonged binding to the parietal H+/K+-ATPase enzyme. The inhibitory effect of Rabeprazole Sodium on acid secretion increases slightly with repeated once-daily dosing, achieving steady state inhibition after three days. When the drug is discontinued, secretory activity normalizes over 2 to 3 days.
Serum Gastrin Effects: In clinical studies patients were treated once daily with 10 or 20 mg Rabeprazole Sodium, for up to 24 months duration. Serum gastrin levels increased during the first 2 to 8 weeks reflecting the inhibitory effects on acid secretion. Gastrin values returned to pretreatment levels, usually within 1 to 2 weeks after discontinuation of therapy.
Pharmacokinetics: Rabeprazole Sodium is acid-labile, and is therefore administered orally as an enteric-coated (gastro-resistant) tablet formulation. Absorption of Rabeprazole Sodium therefore begins only after the tablet leaves the stomach. Absorption is rapid, with peak plasma levels of Rabeprazole Sodium occurring approximately 3.5 hours after a 20 mg dose. Peak plasma concentrations (Cmax) of Rabeprazole Sodium and AUC are linear over the dose range of 10 mg to 40 mg. Absolute bioavailability of an oral 20 mg dose (compared to intravenous administration) is about 52% due in large part to pre systemic metabolism. The absolute bioavailability upon oral administration is robust against food intake or administration of antacids. In healthy subjects the plasma half-life is approximately one hour (range 0.7 to 1.5 hours), and the total body clearance is estimated to be 283 ± 98 mL/min. In patients with chronic hepatic disease, the AUC doubled compared to healthy volunteers, reflecting a decreased first pass effect, and the plasma half-life increased 2-3 fold. Rabeprazole Sodium is approximately 97% bound to human plasma proteins. Rabeprazole Sodium undergoes an almost complete, mainly non enzymatic metabolism and forms thioether-Rabeprazole. The main plasma metabolites are thioether (M1) and carboxylic acid (M6). Minor metabolites observed at lower levels include sulphone (M2), desmethyl-thioether (M4) and mercapturic acid conjugate (M5). Only the desmethyl metabolite (M3) has a small amount of antisecretory activity, but it is not present in plasma. Excretion is mainly urinary (90%), with no unchanged drug excreted in the urine. The rest of the metabolites are excreted via the feces. Total recovery was 99.8% implying a low biliary excretion of the metabolites of Rabeprazole Sodium. All PPls except Rabeprazole Sodium, are metabolized primarily by the hepatic cytochrome P450 enzyme system, and common genetic polymorphisms of the CYP 2C19 isoenzyme affect their clearance and bioavailability. This has been demonstrated to lead to inconsistency in terms of acid suppression across the CYP 2C19 genotypes for all proton pump inhibitors except for Rabeprazole Sodium. Genetic polymorphisms for CYP2C19 do not significantly influence Rabeprazole Sodium clearance, clinical efficacy or potential for drug interactions. In patients with stable, end-stage, renal failure requiring maintenance haemodialysis (creatinine clearance <5 mL/min/1.73 m2), the disposition of Rabeprazole Sodium was very similar to that in healthy volunteers. Elimination of Rabeprazole Sodium was somewhat decreased in the elderly. Following 7 days of daily dosing with 20 mg of Rabeprazole Sodium, the AUC approximately doubled, the Cmax increased by 60% as compared to young healthy volunteers. However there was no evidence of Rabeprazole Sodium accumulation.
