Rabeprazole

Warfarin: Potential pharmacokinetic interaction. Proton-pump inhibitors may inhibit warfarin metabolism. No clinically important interaction in single-dose studies, but increased international normalized ration (INR) and prothrombin time (PT) have been reported in patients receiving these drugs concomitantly; may need to monitor INR and PT during concomitant use with rabeprazole.

Rabeprazole may increase gastrointestinal pH; concurrent use /of digoxin/ with rabeprazole resulted in increase of the serum peak concentration by 29% in normal subjects.

Rabeprazole may increase gastrointestinal pH; concurrent use /of ketoconazole/ with rabeprazole resulted in 30% reduction in bioavailability.

In vitro incubations employing human liver microsomes indicated that rabeprazole inhibited cyclosporine metabolism with an IC50 of 62 micromolar, a concentration that is over 50 times higher than the Cmax in healthy volunteers following 14 days of dosing with 20 mg of rabeprazole. This degree of inhibition is similar to that by omeprazole at equivalent concentrations.

Combined administration consisting of rabeprazole, amoxicillin, and clarithromycin resulted in increases in plasma concentrations of rabeprazole and 14-hydroxyclarithromycin.

Despite its wide use, rabeprazole has only rarely been associated with hepatic injury. In large scale, long term trials of rabeprazole, serum ALT elevations occurred in less than 1% of patients and at rates similar to those with placebo or comparator drugs. In large case series of drug induced liver injury, rabeprazole has accounted for few instances of symptomatic acute liver injury. Only a few cases of clinically apparent liver disease due to rabeprazole have been published and the characteristics of the injury have not been well defined, but appear to be similar to the features of hepatic injury associated with other proton pump inibitors. Clinically apparent liver injury due to proton pump inhibitors typically arises within the first 4 weeks of treatment with symptoms of jaundice, nausea and fatigue and a hepatocellular or mixed pattern of serum enzyme elevations. Recovery is typically rapid upon withdrawal of the agent. Rash, fever and eosinophilia are rare, as is autoantibody formation. Instances of recurrence on rechallenge have been reported.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 2,500(SRC), determined from a structure estimation method(2), indicates that rabeprazole is expected to have slight mobility in soil(SRC). Volatilization of rabeprazole from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.2X10-17 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Rabeprazole is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.2X10-15 mm Hg(SRC), determined from a fragment constant method(4). Biodegradation data were not available(SRC, 2005).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 2,500(SRC), determined from a structure estimation method(2), indicates that rabeprazole is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 2.1X10-17 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 1.6(SRC), from an estimated log Kow of 1.17(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data were not available(SRC, 2005).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), rabeprazole, which has an estimated vapor pressure of 2.2X10-15 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase rabeprazole may be removed from the air by wet and dry deposition(SRC). Rabeprazole does not contain chromophores that absorb at wavelengths >290 nm and therefore should not be susceptible to direct photolysis from sunlight.

Using a structure estimation method based on molecular connectivity indices(1), the Koc for rabeprazole can be estimated to be 2,500(SRC). According to a classification scheme(2), this estimated Koc value suggests that rabeprazole is expected to have slight mobility in soil.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

rabeprazole

DILI Positive

Oral

DOI:10.1016/j.drudis.2019.09.022

An estimated BCF of 1.6 was calculated for rabeprazole(SRC), using an estimated log Kow of 1.17(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC), provided the compound is not altered physically or chemically once released into the environment(SRP).

The Henry's Law constant for rabeprazole is estimated as 1.2X10-17 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that rabeprazole is expected to be essentially nonvolatile from moist soil and water surfaces(2). Rabeprazole is not expected to volatilize from dry soil surfaces(SRC) based upon a an estimated vapor pressure of 2.2X10-15 mm Hg(SRC), determined from a fragment constant method(3).

/LABORATORY ANIMALS: Acute Exposure/ Single oral doses of rabeprazole at 786 mg/kg and 1024 mg/kg were lethal to mice and rats, respectively. The single oral dose of 2000 mg/kg was not lethal to dogs. The major symptoms of acute toxicity were hypoactivity, labored respiration, lateral or prone position and convulsion in mice and rats and watery diarrhea, tremor, convulsion and coma in dogs.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ In a 88/104-week carcinogenicity study in CD-1 mice, rabeprazole at oral doses up to 100 mg/kg/day did not produce any increased tumor occurrence. The highest tested dose produced a systemic exposure to rabeprazole (AUC) of 1.40 ug.hr/mL

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ In a 104-week carcinogenicity study in Sprague-Dawley rats, males were treated with oral doses of 5, 15, 30 and 60 mg/kg/day and females with 5, 15, 30, 60 and 120 mg/kg/day. Rabeprazole produced gastric enterochromaffin-like (ECL) cell hyperplasia in male and female rats and ECL cell carcinoid tumors in female rats at all doses including the lowest tested dose. The lowest dose (5 mg/kg/day) produced a systemic exposure to rabeprazole (AUC) of about 0.1 ug.hr/mL ... In male rats, no treatment related tumors were observed at doses up to 60 mg/kg/day producing a rabeprazole plasma exposure (AUC) of about 0.2 ug.hr/mL

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Teratology studies have been performed in rats at intravenous doses up to 50 mg/kg/day (plasma AUC of 11.8 ug.hr/mL ...) and rabbits at intravenous doses up to 30 mg/kg/day (plasma AUC of 7.3 ug.hr/mL...) and have revealed no evidence of impaired fertility or harm to the fetus due to rabeprazole.

For more Non-Human Toxicity Excerpts (Complete) data for RABEPRAZOLE (6 total), please visit the HSDB record page.

Rabeprazole is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(1). Based on the UV specta of 1H-benzimidazole(2), rabeprazole does not contain chromophores that absorb UV light at wavelengths >290 nm and therefore should not be susceptible to direct photolysis from sunlight(SRC).

Occupational exposure to rabeprazole may occur through inhalation and dermal contact with this compound at workplaces where rabeprazole is produced or used. Exposure to the drug among the general population may be limited to those being administered rabeprazole calcium, (an antiulcerative). (SRC)

1-2 hours (in plasma)

The plasma half-life ranges from 1 to 2 hours.

The study was designed to determine the absolute bioavailability of 20 mg rabeprazole tablets in normal, healthy subjects in comparison with intravenous administration of 20 mg rabeprazole. ... Each subject was randomized at the beginning of the study to receive either a single 20 mg dose of rabeprazole intravenously or orally during Period 1. ... Intravenous dose was given in constant infusion over five minutes. ... The elimination half-life of rabeprazole sodium (1.47 +/- 0.82 hr) after oral administration was significantly longer than the elimination half-life after intravenous administration (1.02 +/- 0.63 hr), probably due to slower rate of absorption than that of elimination.

Hepatic

Approximately 90% of the rabeprazole dose is excreted in the urine as metabolites. These metabolites are mainly thioether carboxylic acid (TCA), the glucuronide of TCA, and mercapturic acid.

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 P450 3A (CYP3A) to a sulphone metabolite and cytochrome P450 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 sub-populations (e.g. 3 to 5% of Caucasians and 17 to 20% of Asians). Rabeprazole metabolism is slow in these sub-populations, therefore, they are referred to as poor metabolizers of the drug.

Rabeprazole is a known human metabolite of Rabeprazole (rabeprazole_thioether).

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RABEPRAZOLE

Established Pharmacologic Class [EPC] - Proton Pump Inhibitor

Mechanisms of Action [MoA] - Proton Pump Inhibitors

Rabeprazole is a Proton Pump Inhibitor. The mechanism of action of rabeprazole is as a Proton Pump Inhibitor.

RABEPRAZOLE

Various agents with different action mechanisms used to treat or ameliorate PEPTIC ULCER or irritation of the gastrointestinal tract. This has included ANTIBIOTICS to treat HELICOBACTER INFECTIONS; HISTAMINE H2 ANTAGONISTS to reduce GASTRIC ACID secretion; and ANTACIDS for symptomatic relief.

Compounds that inhibit H(+)-K(+)-EXCHANGING ATPASE. They are used as ANTI-ULCER AGENTS and sometimes in place of HISTAMINE H2 ANTAGONISTS for GASTROESOPHAGEAL REFLUX.

Absolute bioavailability is approximately 52%.

Following a single 20 mg oral dose of 14C-labeled rabeprazole, approximately 90% of the drug was eliminated in the urine, primarily as thioether carboxylic acid; its glucuronide, and mercapturic acid metabolites.

Elimination: Normal renal function: Approximately 1 to 2 hours. Hepatic function impairment: 2 to 6 hours.

Protein binding: Very high; approximately 96% bound to human plasma protein.

Since rabeprazole is acid-labile, it is administered as a delayed-release tablet so that it can pass through the stomach relatively intact. Once rabeprazole has left the stomach, absorption occurs within 1 hour of administration. The bioavailability is approximately 52%.

It is unknown whether rabeprazole is distributed into human milk. However, in lactating rats, levels of rabeprazole were 2 to 7 times higher in milk than in blood.