Rabeprazole - How It Works
Clinical pharmacology details from the US FDA-approved label: how Rabeprazole works in your body, how it's absorbed, how long it stays active, and how it's eliminated.
Mechanism of Action
12.1 Mechanism of Action Rabeprazole belongs to a class of antisecretory compounds (substituted benzimidazole proton-pump inhibitors) that do not exhibit anticholinergic or histamine H 2 -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.
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Rabeprazole belongs to a class of antisecretory compounds (substituted benzimidazole proton-pump inhibitors) that do not exhibit anticholinergic or histamine H 2 -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.
12.2 Pharmacodynamics Antisecretory Activity The antisecretory effect begins within one hour after oral administration of 20 mg rabeprazole sodium delayed-release tablets.
The median inhibitory effect of rabeprazole on 24 hour gastric acidity is 88% of maximal after the first dose.
A 20 mg dose of rabeprazole sodium delayed-release tablets 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% ( see table below ).
This relatively prolonged pharmacodynamic action compared to the short pharmacokinetic half-life (1 to 2 hours) reflects the sustained inactivation of the H + , K + ATPase.
Table 3: Gastric Acid Parameters: Rabeprazole Sodium Delayed-Release Tablets versus Placebo After 7 Days of Once Daily Dosing *(p<0.01 versus placebo) Parameter Rabeprazole sodium delayed-release tablets (20 mg once daily) Placebo Basal Acid Output (mmol/hr) 0.4* 2.8 Stimulated Acid Output (mmol/hr) 0.6* 13.3 % Time Gastric pH>3 65* 10 Compared to placebo, 10 mg, 20 mg, and 40 mg of rabeprazole sodium delayed-release tablets, administered once daily for 7 days significantly decreased intragastric acidity with all doses for each of four meal-related intervals and the 24-hour time period overall.
In this study, there were no statistically significant differences between doses; however, there was a significant dose-related decrease in intragastric acidity.
The ability of rabeprazole to cause a dose-related decrease in mean intragastric acidity is illustrated below.
Table 4: AUC Acidity (Mmol • Hr/L): Rabeprazole Sodium Delayed-Release Tablets versus Placebo on Day 7 of Once Daily Dosing (Mean±SD) *(p<0.001 versus placebo) Rabeprazole sodium delayed-release tablets AUC interval (hrs) 10 mg (N=24) 20 mg (N=24) 40 mg (N=24) Placebo (N=24) 08:00 to 13:00 19.6±21.5* 12.9±23* 7.6±14.7* 91.1±39.7 13:00 to 19:00 5.6±9.7* 8.3±29.8* 1.3±5.2* 95.5±48.7 19:00 to 22:00 0.1±0.1* 0.1±0.06* 0.0±0.02* 11.9±12.5 22:00 to 08:00 129.2±84* 109.6±67.2* 76.9±58.4* 479.9±165 AUC 0 to 24 hours 155.5±90.6* 130.9±81* 85.8±64.3* 678.5±216 After administration of 20 mg rabeprazole sodium delayed-release tablets once daily for eight days, the mean percent of time that gastric pH greater than 3 or gastric pH greater than 4 after a single dose (Day 1) and multiple doses (Day 8) was significantly greater than placebo (see table below) .
The decrease in gastric acidity and the increase in gastric pH observed with 20 mg rabeprazole sodium delayed-release tablets administered once daily for eight days were compared to the same parameters for placebo, as illustrated below: Table 5: Gastric Acid Parameters Rabeprazole Sodium Delayed-Release Tablets Once Daily Dosing versus Placebo on Day 1 and Day 8 a No inferential statistics conducted for this parameter. b Gastric pH was measured every hour over a 24-hour period. * (p<0.001 versus placebo) Rabeprazole sodium delayed-release tablets 20 mg once daily Placebo Parameter Day 1 Day 8 Day 1 Day 8 Mean AUC 0 to 24 Acidity 340.8* 176.9* 925.5 862.4 Median trough pH (23-hr) a 3.77 3.51 1.27 1.38 % Time Gastric pH greater than 3 b 54.6* 68.7* 19.1 21.7 % Time Gastric pH greater than 4 b 44.1* 60.3* 7.6 11.0 Effects on Esophageal Acid Exposure In patients with GERD and moderate to severe esophageal acid exposure, a dose of 20 mg and 40 mg per day of rabeprazole sodium delayed-release tablets decreased 24-hour esophageal acid exposure.
After seven days of treatment, the percentage of time that the esophageal pH was less than 4 decreased from baselines of 24.7% for 20 mg and 23.7% for 40 mg, to 5.1% and 2.0%, respectively.
Normalization of 24-hour intraesophageal acid exposure was correlated to gastric pH greater than 4 for at least 35% of the 24-hour period; this level was achieved in 90% of subjects receiving rabeprazole sodium 20 mg and in 100% of subjects receiving rabeprazole sodium 40 mg.
With rabeprazole sodium 20 mg and 40 mg per day, significant effects on gastric and esophageal pH were noted after one day of treatment, and more pronounced after seven days of treatment.
Effects on Serum Gastrin The median fasting gastrin level increased in a dose-related manner in patients treated once daily with rabeprazole sodium delayed-release tablets for up to eight weeks for ulcerative or erosive esophagitis and in patients treated for up to 52 weeks to prevent recurrence of disease.
The group median values stayed within the normal range.
Pharmacokinetics
12.3 Pharmacokinetics After oral administration of 20 mg rabeprazole sodium delayed-release tablets, peak plasma concentrations (C max ) of rabeprazole occur over a range of 2 to 5 hours (T max ). The rabeprazole C max 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. Absorption Absolute bioavailability for a 20 mg oral tablet of rabeprazole (compared to intravenous administration) is approximately 52%. When rabeprazole sodium delayed-release tablets are administered with a high fat meal, T max is variable; which concomitant food intake may delay the absorption up to 4 hours or longer. However, the C max and the extent of rabeprazole absorption (AUC) are not significantly altered. Thus rabeprazole sodium delayed-release tablets may be taken without regard to timing of meals. Distribution Rabeprazole is 96.3% bound to human plasma proteins. Elimination Metabolism: Rabeprazole is extensively metabolized. A significant portion of rabeprazole is metabolized via systemic nonenzymatic reduction to a thioether compound. Rabeprazole is also metabolized to sulphone and desmethyl compounds via cytochrome P450 in the liver. The thioether and sulphone are the primary metabolites measured in human plasma. These metabolites were not observed to have significant antisecretory activity. In vitro studies have demo