Effect of food on the pharmacokinetics of omeprazole, pantoprazole and rabeprazole.

BACKGROUND: The pharmacokinetics of proton pump inhibitors (PPIs) may be affected by food intake. We aimed to evaluate the effect of food on the pharmacokinetics of omeprazole, rabeprazole, and pantoprazole. SETTING: The study population comprised 186 healthy volunteers participating in 6 bioequivalence clinical trials. METHOD: Subjects were evaluated to determine the effect of a high-fat breakfast on the pharmacokinetics of omeprazole (n = 36), rabeprazole (n = 69), and pantoprazole (n = 81). MAIN OUTCOME MEASURE: Drug plasma concentrations were measured using high-performance liquid chromatography coupled to mass spectrometry. RESULTS: Food affected the pharmacokinetics of omeprazole (increased Tmax and decreased AUC and Cmax), pantoprazole (increased Tmax and decreased AUC), and rabeprazole (increased Tmax, Cmax and half-life). Food increased variability in Tmax for all 3 drugs, delaying absorption around 3 to 4 h and until 20 h in some subjects. CONCLUSION: As food delays the absorption of PPIs and increases their variability, it would be better to administer these drugs under fasting conditions. TRIAL REGISTRATION: European Union Drug Regulating Authorities Clinical Trials Database: EudraCT : 2004-003863-59 (registration date 05/MAR/2004), EudraCT 2006-001162-17 (registration date 17-MAR-2006), EudraCT: 2007-002489-37 (registration date 12-JUN-2007), EudraCT: 2007-002490-31 (registration date 12-JUN-2007), EudraCT: 2010-024029-19 (registration date 23-NOV-2010).

Simultaneous enantioselective determination of omeprazole, rabeprazole, lansoprazole, and pantoprazole enantiomers in human plasma by chiral liquid chromatography-tandem mass spectrometry.

Proton pump inhibitors, including omeprazole, rabeprazole, lansoprazole, and pantoprazole, achieved simultaneous enantioselective determination in the human plasma by chiral liquid chromatography-tandem mass spectrometry. The four corresponding stable isotope-labeled proton pump inhibitors were adopted as the internal standards. Each enantiomer and the internal standards were extracted with acetonitrile containing 0.1% ammonia, then separated with a Chiralpak IC column (5 µm, 4.6 mm × 150 mm) within 10 min. The mobile phase was composed of acetonitrile-ammonium acetate (10 mM) containing 0.2% acetic acid (50:50, v/v). To quantify all enantiomers, an API 4000 tandem mass spectrometer was used, and multiple reaction monitoring transitions were performed on m/z 360.1→242.1, 384.1→200.1, 370.1→252.1, and 346.1→198.1, respectively. No significant matrix effect was observed for all analytes. The calibration curve for all enantiomers were linear from 1.25 to 2500 ng/mL. The precisions for intra- and inter-run were < 14.2%, and the accuracy fell in the interval of -5.3 to 8.1%. Stability of samples was confirmed under the storage and processing conditions. The developed method was also suitable for separation and determination of ilaprazole enantiomers. The validated method combining the equilibrium dialysis method was applied to the protein binding ratio studies of four pairs proton pump inhibitor enantiomers in human plasma.

Stereoselective pharmacokinetics of (R)-(+)- and (S)-(-)-rabeprazole in human using chiral LC-MS/MS after administration of rabeprazole sodium enteric-coated tablet.

Rabeprazole is an effective proton pump inhibitor to treat acid-related diseases. To achieve the simultaneous determination of rabeprazole enantiomers in human plasma, a chiral LC-MS/MS method was developed and validated. Acetonitrile including 0.1% ammonium were used as protein precipitating agent. Analytes were separated within 8 minutes on a Chiralpak IC column (4.6 mm × 150 mm, 5 µm). The mobile phase was 10 mM ammonium acetate including 0.2% acetic acid-acetonitrile (35:65, v/v). An API 4000 mass spectrometer was used as detector for the analysis, and the multiple reactions monitoring transitions of m/z 360.1 â†’ 242.2 and 346.1 â†’ 198.1 were opted for quantifying rabeprazole enantiomers and internal standard. Matrix effects were not apparent for each enantiomer and internal standard (esomeprazole), the calibration curves were linear over the concentration of 0.500 to 400 ng·mL-1 , the intra-run precisions were below 5.4%, the inter-run precisions were below 9.9%, and the accuracy was between -9.2% and 9.3%. There was no chiral inversion observed during sample storage, preparation procedure, and analysis, demonstrating that analytes were stable in this study. This method was applied to the stereoselective pharmacokinetic study of (R)-(+)- and (S)-(-)-rabeprazole after oral administration of 10-mg rabeprazole sodium enteric-coated tablet in healthy Chinese subjects.

Determination of rabeprazole enantiomers in dog plasma by supercritical fluid chromatography tandem mass spectrometry and its application to a pharmacokinetic study.

Rabeprazole is a novel benzimidazole proton pump inhibitor used for the treatment of gastrointestinal disorders. It is a chiral molecule that gives rise to the possibility of stereoselective pharmacokinetics. To investigate this phenomenon, a rapid and sensitive chiral assay based on supercritical fluid chromatography tandem mass spectrometry was developed and applied to the determination of (R)-rabeprazole and (S)-rabeprazole in dog plasma. Sample preparation involved protein precipitation with acetonitrile after the addition of (R)-lansoprazole as internal standard. Baseline separation of enantiomers in 4.5 min was achieved on an Acquity UPC2 system using an ACQUITY UPC2 Trefoil CEL2 column maintained at 60°C and a mobile phase consisting of methanol/CO2 (30:70, v/v) delivered at 2.5 mL/min. Detection was achieved by multiple reaction monitoring of the transitions at m/z 360.0→242.2 (rabeprazole) and 370.3→252.0 (internal standard) in the positive ion mode. The assay was linear in the range of 1-1000 ng/mL and free of matrix effects. Intra- and interday precisions were less than 10.0% with accuracy in the range of -2.6 to 3.1%. The method was successfully applied to a pharmacokinetic study of rabeprazole enantiomers after administration of a single oral dose of 10 mg racemate to beagle dogs.

Effect of netazepide, a gastrin/CCK2 receptor antagonist, on gastric acid secretion and rabeprazole-induced hypergastrinaemia in healthy subjects.

AIMS: To compare gastric acid suppression by netazepide, a gastrin/CCK2 receptor antagonist, with that by a proton pump inhibitor (PPI), and to determine if netazepide can prevent the trophic effects of PPI-induced hypergastrinaemia. METHODS: Thirty healthy subjects completed a double-blind, randomized, parallel group trial of oral netazepide and rabeprazole, alone and combined, once daily for 6 weeks. Primary end points were: basal and pentagastrin-stimulated gastric acid and 24 h circulating gastrin and chromogranin A (CgA) at baseline, start and end of treatment, gastric biopsies at baseline and end of treatment and basal and pentagastrin-stimulated gastric acid and dyspepsia questionnaire after treatment withdrawal. RESULTS: All treatments similarly inhibited pentagastrin-stimulated gastric acid secretion. All treatments increased serum gastrin, but the combination and rabeprazole did so more than netazepide alone. The combination also reduced basal acid secretion. Rabeprazole increased plasma CgA, whereas netazepide and the combination reduced it. None of the biopsies showed enterochromaffin-like (ECL) cell hyperplasia. Withdrawal of treatments led neither to rebound hyperacidity nor dyspepsia. CONCLUSIONS: Netazepide suppressed pentagastrin-stimulated gastric acid secretion as effectively as did rabeprazole. The reduction in basal acid secretion and greater increase in serum gastrin by the combination is consistent with more effective acid suppression. Despite our failure to show rabeprazole-induced ECL cell hyperplasia and rebound hyperacidity, the increase in plasma CgA after rabeprazole is consistent with a trophic effect on ECL cells, which netazepide prevented. Thus, netazepide is a potential treatment for the trophic effects of hypergastrinaemia and, with or without a PPI, is a potential treatment for acid-related conditions.

The use of betaine HCl to enhance dasatinib absorption in healthy volunteers with rabeprazole-induced hypochlorhydria.

Many orally administered, small-molecule, targeted anticancer drugs, such as dasatinib, exhibit pH-dependent solubility and reduced drug exposure when given with acid-reducing agents. We previously demonstrated that betaine hydrochloride (BHCl) can transiently re-acidify gastric pH in healthy volunteers with drug-induced hypochlorhydria. In this randomized, single-dose, three-way crossover study, healthy volunteers received dasatinib (100 mg) alone, after pretreatment with rabeprazole, and with 1500 mg BHCl after rabeprazole pretreatment, to determine if BHCl can enhance dasatinib absorption in hypochlorhydric conditions. Rabeprazole (20 mg b.i.d.) significantly reduced dasatinib Cmax and AUC0-∞ by 92 and 78%, respectively. However, coadministration of BHCl significantly increased dasatinib Cmax and AUC0-∞ by 15- and 6.7-fold, restoring them to 105 and 121%, respectively, of the control (dasatinib alone). Therefore, BHCl reversed the impact of hypochlorhydria on dasatinib drug exposure and may be an effective strategy to mitigate potential drug-drug interactions for drugs that exhibit pH-dependent solubility and are administered orally under hypochlorhydric conditions.

Population pharmacokinetics of rabeprazole and dosing recommendations for the treatment of gastroesophageal reflux disease in children aged 1-11 years.

BACKGROUND AND OBJECTIVE: Rabeprazole sodium is a proton pump inhibitor used for the treatment of gastroesophageal reflux disease (GERD). The objective of this study was to develop a population pharmacokinetic model for rabeprazole that describes concentration-time data arising from phase I and phase III studies in adult and pediatric subjects, including neonates and preterm infants, and propose dosing recommendations for pediatric subjects aged 1-11 years. METHODS: A total of 4,417 pharmacokinetic observations from 597 subjects aged 6 days to 55.7 years with body weights of 1.15-100 kg were used to develop the population pharmacokinetic model using non-linear mixed-effects modeling techniques. Weight and age were included in the structural model to describe clearance (CL) and central volume of distribution (V c). Other covariates considered during model development included sex, race, creatinine clearance, hepatic function, formulation, feeding status, and route of administration. The final model was used to determine doses for pediatric subjects aged 1-11 years to achieve a steady-state area under the plasma concentration-time curve across the dose interval of 24 h (AUC24) within the target adult AUC24 range obtained following a rabeprazole 10 mg dose. RESULTS: The best model was a two-compartment disposition model with a sequential zero-order duration of input (Dur), first-order absorption (k a) following a lag time (T lag), with weight and age effects on CL and V c. Formulation type and feeding status described some of the variability in bioavailability and the absorption parameters T lag, Dur, and k a. A dosage regimen of 5 mg once daily for children <15 kg, and 10 mg for children ≥15 kg is recommended for 1- to 11-year-old pediatric patients with GERD. CONCLUSIONS: The pharmacokinetics of rabeprazole were described with good precision following administration of rabeprazole across a range of doses and in a range of formulations.

The chiral bioconversion and preclinical pharmacokinetic analysis of (R)-(+)-rabeprazole in beagle dogs by HPLC and HPLC-MS/MS.

In order to accurately investigate the preclinical pharmacokinetics of (R)-(+)-rabeprazole sodium injection, a reliable high-performance liquid chromatography (HPLC) method was developed using a Chiral-AGP column to prove that there is no chiral bioconversion of (R)-(+)-rabeprazole to (S)-(-)-rabeprazole in beagle dogs after single intravenous administration of (R)-(+)-rabeprazole sodium injection. An HPLC-tandem mass spectrometry (HPLC-MS/MS) method for analysis of (R)-(+)-rabeprazole was developed and validated, and used to acquire the pharmacokinetic parameters in beagle dogs. (R)-(+)-Rabeprazole and internal standard omeprazole were extracted from plasma samples by protein precipitation and separated on a C18 column using methanol-5 mm ammonium acetate as mobile phase. Detection was performed using a turbo-spray ionization source and mass spectrometric positive multi-reaction monitoring mode. The linear relationship was achieved in the range from 2.5 to 5000 ng/mL. The method also afforded satisfactory results in terms of sensitivity, specificity, precision, accuracy and recovery as well as the stability of the analyte under various conditions, and was successfully applied to a preclinical pharmacokinetic study in beagle dogs after single intravenous administrations of (R)-(+)-rabeprazole sodium injection at 0.33, 2 and 6 mg/kg.