Rablet-D Mechanism of Action

Pharmacology: Mechanism of Action: 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 sulfonamide. When studied in vitro, rabeprazole is chemically activated at pH 1.2 with a half-life (t_½) of 78 sec. It inhibits acid transport in porcine gastric vesicles with a t_½ of 90 sec.
Antisecretory Activity: The antisecretory effect begins within 1 hr after oral 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 vs 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 t_½ (1-2 hr) reflects the sustained inactivation of the H⁺, K⁺ATPase.
Compared to placebo, rabeprazole 10, 20 and 40 mg administered once daily for 7 days significantly decreased intragastric acidity with all doses for each of 4 meal-related intervals and the 24-hr 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.
After administration of rabeprazole 20 mg once daily for 8 days, the mean percent of time that gastric pH >3 or gastric pH >4 alter a single dose (Day 1) and multiple doses (Day 8) was significantly greater than placebo.
Effects on Esophageal Acid Exposure: In patients with gastroesophageal reflux disease (GERD) and moderate to severe esophageal acid exposure, rabeprazole 20- and 40 mg/day decreased 24-hr esophageal acid exposure. After 7 days of treatment, the percentage of time that esophageal pH <4 decreased from baselines of 24.7% for 20 mg and 23.7% for 40 mg, to 5.1% and 2%, respectively. Normalization of 24-hr intraesophageal acid exposure was correlated to gastric pH >4 for at least 35% of the 24-hr period; this level was achieved in 90% of subjects receiving rabeprazole 20 mg and in 100% of subjects receiving rabeprazole 40 mg. With rabeprazole 20- and 40 mg/day, significant effects on gastric and esophageal pH were noted after 1 day of treatment and more pronounced after 7 days of treatment.
Effects on Serum Gastrin: In patients given daily doses of rabeprazole for up to 8 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.
In a group of subjects treated daily with rabeprazole 20 mg for 4 weeks, a doubling of mean serum gastrin concentrations were observed. Approximately 35% of these treated subjects developed serum gastrin concentrations above the upper limit of normal (ULN).
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.
In over 400 patients treated with rabeprazole (10 or 20 mg/day) for up to 1 year, the incidence of ECL cell hyperplasia increased with time and dose, which is consistent with the pharmacological action of the proton-pump inhibitor. No patient developed the adenomatoid, dysplastic or neoplastic changes of ECL cells in the gastric mucosa. No patient developed the carcinoid tumors observed in rats.
Endocrine Effects: Studies in humans for up to 1 year have not revealed clinically significant effects on the endocrine system. In healthy male volunteers treated with rabeprazole for 13 days, no clinically relevant changes have been detected in the following endocrine parameters examined: 17β-estradiol, thyroid-stimulating hormone, triiodothyronine, thyroxine, thyroxine-binding protein, parathyroid hormone, insulin, glucagon, renin, aldosterone, follicle-stimulating hormone, luteotrophic hormone, prolactin, somatotrophic hormone, dehydroepiandrosterone, cortisol-binding globulin and urinary 6β-hydroxycortisol, serum testosterone and circadian cortisol profile.
Other Effects: In humans treated with rabeprazole for up to 1 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.
Domperidone: It is a dopamine antagonist with anti-emetic properties. Its anti-emetic effect may be due to a combination of peripheral (gastrokinetic) effects and antagonism of dopamine receptors in the chemoreceptor trigger zone, which lies outside the blood-brain barrier in the area postrema. Animal studies, together with low concentrations found in the brain, indicate a predominantly peripheral effect of domperidone on dopamine receptors. Studies in man have shown oral domperidone to increase lower oesophageal pressure, improve antroduodenal motility and accelerate gastric emptying. There is no effect on gastric secretion. Domperidone does not readily cross the blood-brain barrier. In domperidone users, especially in adults, extrapyramidal side effects are very rare, but domperidone promotes the release of prolactin from the pituitary.
Pharmacokinetics: Rablet D is enteric-coated to allow rabeprazole sodium to pass through the stomach relatively intact. After oral administration of rabeprazole 20 mg, peak plasma concentrations (C_max) of rabeprazole occur over a range of 2-5 hrs (T_max). The rabeprazole C_max and AUC are linear over an oral dose range of 10-40 mg. 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 (t_½) ranges from 1-2 hrs. Absolute bioavailability for rabeprazole 20 mg oral tablet (compared to IV administration) is approximately 52%. When rabeprazole is administered with a high fat meal, its T_max is variable and may delay its absorption up to 5 hrs or longer, however, the C_max and the extent of rabeprazole absorption (AUC) are not significantly altered. Thus, rabeprazole may be taken without regard to timing of meals.
Rabeprazole is 96.3% bound to human plasma proteins.
Rabeprazole is extensively metabolized. 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 demonstrated that rabeprazole is metabolized in the liver primarily by cytochromes P-450 3A (CYP3A) to a sulphone metabolite and cytochrome P-450 2C19 (CYP2C19) to desmethyl rabeprazole. The thioether metabolite is formed non-enzymatically by reduction of rabeprazole. CYP2C19 exhibits a known genetic polymorphism due to its deficiency in some subpopulations (eg, 3-5% of Caucasians and 17-20% of Asians). Rabeprazole metabolism is slow in these subpopulations, therefore, they are referred to as poor metabolizers of the drug.
Following a single oral dose of 14C-labeled rabeprazole 20 mg, 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. Total recovery of radioactivity was 99.8%. No unchanged rabeprazole was recovered in the urine or feces.
Special Populations: Geriatric: In 20 healthy elderly subjects administered rabeprazole 20 mg once daily for 7 days, AUC values approximately doubled and the C_max increased by 60% compared to values in a parallel younger control group. There was no evidence of drug accumulation after once daily administration (see Precautions).
Pediatric: The pharmacokinetics of rabeprazole in pediatric patients <18 years have not been studied.
Gender and Race: In analyses adjusted for body mass and height, rabeprazole pharmacokinetics showed no clinically significant differences between male and female subjects. In studies that used different formulations of rabeprazole, AUC values for healthy Japanese men were approximately 50-60% greater than values derived from pooled data from healthy men in the United States.
Renal Insufficiency: In 10 patients with stable end-stage renal disease requiring maintenance hemodialysis [creatinine clearance (CrCl) ≤5 mL/min/1.73 m²], no clinically significant differences were observed in the pharmacokinetics of rabeprazole after a single 20 mg oral dose when compared to 10 healthy volunteers.
Hepatic Insufficiency: In a single dose study of 10 patients with chronic mild to moderate compensated cirrhosis of the liver who were administered a dose of rabeprazole 20 mg, AUC_0-24 was approximately doubled, the elimination t_½ was 2- to 3-fold higher and the total body clearance was decreased to less than half compared to values in healthy men.
In a multiple dose study of 12 patients with mild to moderate hepatic impairment administered rabeprazole 20 mg once daily for 8 days, AUC and C_max values increased approximately 20% compared to values in healthy age- and gender-matched subjects. These increases were not statistically significant.
No information exists on rabeprazole disposition in patients with severe hepatic impairment.
Domperidone: In fasting subjects, domperidone is rapidly absorbed after oral administration, with peak plasma concentrations at 30-60 min. The low absolute bioavailability of oral domperidone (approximately 15%) is due to an extensive first-pass metabolism in the gut wall and liver. Although domperidone's bioavailability is enhanced in normal subjects when taken after meal, patients with gastrointestinal complaints should take domperidone 15-30 min before a meal. Reduced gastric acidity impairs the absorption of domperidone. Oral bioavailability is decreased by prior concomitant administration of cimetidine and sodium bicarbonate. The time of peak absorption is slightly delayed and the AUC somewhat increased when the oral drug is taken after a meal.
Oral domperidone does not appear to accumulate or induce its own metabolism; a peak plasma level after 90 min of 21 ng/mL after 2 weeks oral administration of 30 mg/day was almost the same as that of 18 ng/mL after the first dose. Domperidone is 91-93% bound to plasma proteins. Distribution studies with radio-labeled drug in animals have shown wide tissue distribution, but low brain concentration. Small amounts of drug cross the placenta in rats.
Domperidone undergoes rapid and extensive hepatic metabolism by hydroxylation and N-dealkylation. In vitro metabolism experiments with diagnostic inhibitors revealed that CYP3A4 is a major form of cytochrome P-450 involved in the N-dealkylation of domperidone, whereas CYP3A4, CYP1A2 and CYP2E1 are involved in domperidone aromatic hydroxylation.
Urinary and faecal excretions amount to 31% and 66% of the oral dose, respectively. The proportion of the drug excreted unchanged is small (10% of faecal excretion and approximately 1% of urinary excretion). The plasma t_½ after a single oral dose is 7-9 hrs in healthy subjects but is prolonged in patients with severe renal insufficiency.