Pharmacology: Pharmacodynamics: 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 if 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 sulfonamide.
Pharmacokinetics: After oral administration of rabeprazole 20 mg, peak plasma concentrations (Cmax) of rabeprazole occur over a range of 2-5 hrs (Tmax). There is no appreciable accumulation when doses of 10-40 mg are administered every 24 hrs; the pharmacokinetics of rabeprazole is not altered by multiple-dosing. The plasma half-life (t½) ranges from 1-2 hrs.
Following oral administration of rabeprazole 20 mg, it is absorbed and can be detected in plasma by 1 hr. Absolute bioavailability for a rabeprazole 20-mg oral compared to IV is about 52%. Rabeprazole is 96.3% bound to human plasma proteins.
Rabeprazole is extensively metabolized. The thioether and sulfone are the primary metabolites measured in human plasma. These metabolites were not observed to have significant antisecretory activity. In vitro studies have demonstrated that rabeprazole is primarily metabolized in the liver by cytochromes P450 (CYP450) 3A (sulfone metabolite) and 2C19 (desmethyl rabeprazole). Approximately, 90% of the drug is eliminated in the urine, primarily as thioether carboxylic acid; its glucuronide and mercapturic acid metabolites.
The antisecretory effect begins within 1 hr after administration of rabeprazole 20 mg. The median inhibitory effect of rabeprazole on 24-hr 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-hr period that the gastric pH >3 from 10-65%. This relatively prolonged pharmacodynamic action compared to the short pharmacokinetic half-life (1-2 hrs) reflects the sustained inactivation of the H+/K+-ATPase.
Injection: These metabolites were not observed to have significant anti-secretory activity. No unchanged rabeprazole is recovered in the urine or faeces.
Capsule: Special Populations: Geriatric: Reported data from clinical studies in healthy elderly subjects indicates that area under the time-concentration (AUC) values are approximately doubled and peak plasma concentration (Cmax) increased by 60% compared to values in a parallel younger control group. There was no evidence of drug accumulation after once daily dosing.
Pediatric: The pharmacokinetics of rabeprazole in pediatric patients has not been studied.
Gender and Race: In analysis of body mass and weight, rabeprazole pharmacokinetics showed no clinically significant differences between male and female volunteers.
Renal Disease: No clinically significant difference was observed in the pharmacokinetics of rabeprazole between healthy volunteers and patients requiring maintenance haemodialysis.
Hepatic Disease: Reported data from single dose clinical study indicates that AUC and elimination half-lives are doubled in patients with mild to moderate liver cirrhosis as compared to healthy volunteers. No information exists on rabeprazole disposition in patients with severe hepatic impairment.