Pariet Mechanism of Action

Pharmacology: Mechanism of Action: Sodium rabeprazole 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 (the acid or proton-pump). The effect is dose-related and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus. Animal studies indicate that after administration, sodium rabeprazole rapidly disappears from both the plasma and gastric mucosa. As a weak base, rabeprazole is rapidly absorbed following all doses and is concentrated in the acid environment of the parietal cells. Rabeprazole is converted to the active sulfonamide form through protonation and it subsequently reacts with the available cysteines on the proton-pump.
Antisecretory Activity: After oral administration of a 20-mg dose of sodium rabeprazole, the onset of antisecretory effect occurs within 1 hr, with the maximum effect occurring within 2-4 hrs. Inhibition of basal and food-stimulated acid secretion 23 hrs after the 1st dose of sodium rabeprazole are 69% and 82%, respectively, and the duration of inhibition lasts up to 48 hrs. The inhibitory effect of sodium rabeprazole on acid secretion increases slightly with repeated once-daily dosing, achieving steady-state inhibition after 3 days. When the drug is discontinued, secretory activity normalizes over 2-3 days.
Serum Gastrin Effects: In clinical studies, patients were treated once daily with 10 or 20 mg sodium rabeprazole, for up to 43 months duration. Serum gastrin levels increased during the first 2-8 weeks reflecting the inhibitory effects on acid secretion and remained stable while treatment was continued. Gastrin values returned to pre-treatment levels, usually within 1-2 weeks after discontinuation of therapy.
Human gastric biopsy specimens from the antrum and the fundus from >500 patients receiving rabeprazole or comparator treatment for up to 8 weeks have not detected changes in ECL cell histology, degree of gastritis, incidence of atrophic gastritis, intestinal metaplasia or distribution of Helicobacter pylori infection. In >250 patients followed for 36 months of continuous therapy, no significant change in findings present at baseline was observed.
Other Effects: Systemic effects of sodium rabeprazole in the central nervous, cardiovascular and respiratory systems have not been found to date. Sodium rabeprazole, given in oral doses of 20 mg for 2 weeks, had no effect on thyroid function, carbohydrate metabolism, or circulating levels of parathyroid hormone, cortisol, estrogen, testosterone, prolactin, cholecystokinin, secretin, glucagon, follicle-stimulating hormone (FSH), luteinizing hormone (LH), renin, aldosterone or somatotrophic hormone.
Pharmacokinetics: Absorption: Pariet is an enteric-coated (gastro-resistant) tablet formulation of sodium rabeprazole. This presentation is necessary because rabeprazole is acid-labile. Absorption of rabeprazole, therefore, begins only after the tablet leaves the stomach. Absorption is rapid, with peak plasma levels of rabeprazole occurring approximately 3.5 hrs after a 20-mg dose. Peak plasma concentrations (C_max) of rabeprazole and AUC are linear over the dose range of 10-40 mg. Absolute bioavailability of an oral 20-mg dose (compared to IV administration) is about 52% due in large part to presystemic metabolism. Additionally, the bioavailability does not appear to increase with repeat administration. In healthy subjects, the plasma half-life is approximately 1 hr (range 0.7-1.5 hrs), and the total body clearance is estimated to be 283±98 mL/min. Neither food nor the time of day of administration of the treatment affects the absorption of sodium rabeprazole.
Distribution: Rabeprazole is approximately 97% bound to human plasma proteins.
Metabolism and Excretion: In humans, the thioether (M1) and carboxylic acid (M6) are the main plasma metabolites with the sulfone (M2), desmethyl-thioether (M4) and mercapturic acid conjugate (M5) minor metabolites observed at lower levels. Only the desmethyl metabolite (M3) has a small amount of antisecretory activity, but it is not present in plasma.
Following a single 20-mg ¹⁴C-labeled oral dose of sodium rabeprazole, no unchanged drug was excreted in the urine. Approximately 90% of the dose was eliminated in urine mainly as the 2 metabolites: A mercapturic acid conjugate (M5) and a carboxylic acid (M6), plus 2 unknown metabolites. The remainder of the dose was recovered in feces.
Gender: Adjusted for body mass and height, there are no significant gender differences in pharmacokinetic parameters following a single 2-mg dose of rabeprazole.
Renal Dysfunction: In patients with stable, end-stage renal failure requiring maintenance hemodialysis (creatinine clearance ≤5 mL/min/1.73 m²), the disposition of rabeprazole was very similar to that in healthy volunteers. The AUC and the C_max in these patients was about 35% lower than the corresponding parameters in healthy volunteers. The mean half-life of rabeprazole was 0.82 hrs in healthy volunteers, 0.95 hrs in patients during hemodialysis and 3.6 hrs post-dialysis. The clearance of the drug in patients with renal disease requiring maintenance hemodialysis was approximately twice that in healthy volunteers.
Hepatic Dysfunction: Following a single 20-mg dose of rabeprazole to patients with chronic mild to moderate hepatic impairment, the AUC doubled and there was a 2- to 3-fold increase in half-life of rabeprazole compared to the healthy volunteers. However, following a 20-mg dose daily for 7 days, the AUC had increased to only 1.5-fold and the C_max to only 1.2-fold. The half-life of rabeprazole in patients with hepatic impairment was 12.3 hrs compared to 2.1 hrs in healthy volunteers. The pharmacodynamic response (gastric pH control) in the 2 groups was clinically comparable.
Elderly: Elimination of rabeprazole was somewhat decreased in the elderly. Following 7 days of daily dosing with 20 mg of sodium rabeprazole, the AUC approximately doubled, the C_max increased by 60% and t_½ increased by approximately 30% as compared to young healthy volunteers. However, there was no evidence of rabeprazole accumulation.
CYP2C19 Polymorphism: Following a 20-mg daily dose of rabeprazole for 7 days, CYP2C19 slow metabolizers had AUC and t_½ which were approximately 1.9 and 1.6 times the corresponding parameters in extensive metabolizers whilst C_max had increased by only 40%.
Toxicology: Preclinical Safety Data: Preclinical effects were observed only at exposures sufficiently in excess of the maximum human exposure that make concerns for human safety negligible in respect of animal data.
Studies on mutagenicity gave equivocal results. Tests in mouse lymphoma cell line were positive, but in vivo micronucleus and in vivo and in vitro DNA repair tests were negative. Carcinogenicity studies revealed no special hazard for humans.