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Omeprazole, a gastric acid pump inhibitor, is repeatedly administered and is oxidatively metabolized mainly by polymorphic cytochrome P450 2C19. The prescribed dosage of omeprazole was discontinued or reduced in 47 of the 135 patients who received omeprazole alone in this survey, as recorded in the Japanese Adverse Drug Event Report database. The days to onset of omeprazole-related disorders were 3-4 d (median) and 16 d for intravenous 20-40 mg and oral 20 mg daily doses, respectively, in 34 patients for whom relevant data were available. The maximum plasma concentration of omeprazole was pharmacokinetically modeled after a single oral 40-mg dose in P450 2C19-defective poor metabolizers and was 2.4-fold higher than that in extensive metabolizers. The modeled area under the hepatic concentration curves of omeprazole in P450 2C19 poor metabolizers after virtual daily 40-mg doses for 7 d was 5.2-fold higher than that in the extensive metabolizers. Omeprazole-induced P450 2C19 (approx. 2-fold), resulting in increased hepatic intrinsic clearance in repeated doses, was considered after the second day. Virtual plasma/hepatic exposure estimated using pharmacokinetic modeling in subjects with P450 2C19 poor metabolizers indicated that these exposure levels virtually estimated could be one of causal factors for unexpected hepatic disorders induced by prescribed omeprazole, such as those resulting from drug interactions with repeatedly co-administered medicines.

Renal allograft survival requires multiple immunosuppressive drugs. This strategy may lead to gastric complications that necessitate gastro-protective medications, notably, proton pump inhibitors (PPI). This study aimed to compare the influence of pantoprazole and esomeprazole on serum cyclosporine trough levels (C 0 ) in renal transplant recipients (RTR). A prospective, parallel, open-label trial was conducted on 47 adult RTR receiving cyclosporine doses adjusted to attain trough concentrations of 100 to 150 μg/L, mycophenolate mofetil (MMF) 750 mg q12 hour and prednisolone at 5 mg daily at Nasser Institute, Cairo, Egypt from January to September 2016. Patients were randomized into the esomeprazole group (25) or pantoprazole group (22) receiving the same dose (40 mg once daily). The study outcomes included clinical signs of rejection and renal function decline, assessed by elevations in serum creatinine, caused by cyclosporine level variations in either of the two study groups. Renal function, C 0 and CBC measurements were measured at baseline and monthly for 6 months. The mean C 0 values were higher in the pantoprazole group than in the esomeprazole group in the sixth month only (P = .007). Serum creatinine level was lower in the sixth month than at baseline in the esomeprazole group (P = .004). There were no signs of rejection biochemical or clinical in any of the study groups. In conclusion, PPIs should be used with caution and doses should be titrated to reach the C 0 targets in RTR, which is of more importance in pantoprazole than esomeprazole to avoid C 0 level elevation or decline affecting the allograft function., (© 2019 International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.)

Phosphate binder pill (PBP) burden is a significant problem in dialysis patients. Phosphate absorption through the paracellular pathway increases in relatively acidic pH. In this study, we evaluated the effect of factors contributing to duodenal pH-Helicobacter pylori (HP), proton pump inhibitors (PPIs), and NaHCO 3 capsules-on PBP burden. We evaluated 255 dialysis patients with gastric biopsies and excluded patients with low Kt/V, gastrectomy, and parathyroidectomy. Patients were divided into groups and subgroups regarding HP existence, use of PPI, or NaHCO 3 capsules. HP+ group had significantly higher PBP burden and PBP equivalent doses (P < 0.001; both). HP+ subgroup not using daily PPIs or NaHCO 3 capsules had the highest PBP burden and PBP equivalent doses (P < 0.001; both). HP- subgroups had similar PBP and PBP equivalent doses (P = 0.446 and P = 0.382; respectively). HP colonization might affect the PBP burden in dialysis patients due to a decrease of duodenal pH., (© 2019 International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.)

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 T max and decreased AUC and C max ), pantoprazole (increased T max and decreased AUC), and rabeprazole (increased T max , C max and half-life). Food increased variability in T max 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).

Anaprazole is a novel proton pump inhibitor under development for the treatment of gastric and duodenal ulcers. In the present study, an ultra-performance liquid chromatography-ultraviolet detector/quadrupole time-of-flight mass spectrometry method was developed for the metabolic profiling of human plasma after an oral administration of 40 mg anaprazole. The principal metabolic pathways were identified as sulfoxide reduction to thioether (M8-1), dehydrogenation (M21-1), sulfoxide oxidation to sulfone (M16-3), and sulfoxide reduction with O-demethylation to form carboxylic acid (M7-1). Anaprazole, M8-1, M16-3, M21-1, and M7-1 were selected and further quantified in human plasma by using a rapid and sensitive liquid chromatography-tandem mass spectrometry method. Anaprazole and its four metabolites were extracted from 50 of μL plasma by acetonitrile protein precipitation. Chromatographic retention and separation were achieved on an Kinetex XB-C 18 column (50 mm × 4.6 mm i.d., 5 μm) under gradient elution using 5 mM ammonium acetate with 0.005 % ammonium hydroxide and methanol with 0.005 % ammonium hydroxide as the mobile phase. Positive electrospray ionization was performed using multiple reaction monitoring with transitions of m/z 402.2→242.2, 386.2→226.2, 400.2→242.2, 418.2→282.2, and 386.2→161.2 for anaprazole, M8-1, M21-1, M16-3, and M7-1, respectively. This method was linear in the range of 5.00-3000 ng/mL for anaprazole and 1.00-600 ng/mL for the four metabolites. The lower limit of quantitation was established at 5.00 ng/mL for anaprazole and 1.00 ng/mL for the metabolites. The quantitative method was used to evaluate the pharmacokinetics of anaprazole in phase I clinical trials., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Dispersive micro-solid-phase extraction (DMSPE) combined with dispersive liquid-liquid microextraction based on the solidification of a floating organic droplet (DLLME-SFO) was successfully developed for extraction and depuration of pantoprazole in rat plasma. The remarkable metal organic framework (MOF), MIL-101(Cr) was used as DMSPE adsorbent. The detection of pantoprazole was performed by convenient HPLC-UV. In the extraction of pantoprazole from plasma samples, small molecule compounds, including the target and abundant impurities, were easily admitted into the porous structure of MIL-101 (Cr) material in DMSPE; while, macromolecular compounds were handily excluded from the adsorbent. Next, the depuration process was achieved by removal of small polar impurities in DLLME-SFO. Influential factors were systematically optimized for ideal enrichment and depuration efficiency. Under the optimal conditions, a satisfactory linearity range from the lower limit of quantification (LLOQ, 100 ng/L) to 10 000 ng/L with the correlation coefficients (r) of 0.9934 was obtained. The LLOQ was 100 ng/mL and the relative recoveries were ≧ 73.2 ± 4.8%. The approving reproducibility, acceptable accuracy, and stability were all within the acceptance limits. This proposed method presented the advantages of environment-friendly, low-cost, recyclable, low impurity, and preferable applicability. It could offer a new idea for the pretreatment and pharmacokinetic study of pantoprazole in rat plasma., (Copyright © 2019. Published by Elsevier B.V.)

Regorafenib exposure could potentially be influenced by an interaction with acid-reducing drugs. In this crossover trial, patients were randomized into two sequence groups consisting of three phases: regorafenib intake alone, regorafenib with concomitant esomeprazole, and regorafenib with esomeprazole 3 hours prior. The primary end point was the relative difference (RD) in geometric means for regorafenib 0-24-hour area under the concentration-time curve (AUC 0-24h ) and was analyzed by a linear mixed model in 14 patients. AUC 0-24h for regorafenib alone was 55.9 μg·hour/mL (coefficient of variance (CV): 40%), and for regorafenib with concomitant esomeprazole or with esomeprazole 3 hours prior AUC 0-24h was 53.7 μg·hour/mL (CV: 34%) and 53.6 μg·hour/mL (CV: 43%), respectively. No significant differences were identified when regorafenib alone was compared with regorafenib with concomitant esomeprazole (RD: -3.9%; 95% confidence interval (CI): -20.5 to 16.1%; P = 1.0) or regorafenib with esomeprazole 3 hours prior (RD: -4.1%; 95% CI: -22.8 to 19.2%; P = 1.0). These findings indicate that regorafenib and esomeprazole can be safely combined in clinical practice., (© 2018 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Purpose: Ilaprazole, the latest proton pump inhibitor, can be used with clarithromycin and amoxicillin as a triple therapy regimen for eradicating Helicobacter pylori. The aim of this study was to evaluate pharmacokinetic drug interactions and safety profiles after coadministration of clarithromycin, amoxicillin, and ilaprazole., Methods: A randomised, open-label, one-way crossover, two parallel sequences study was conducted in 32 healthy subjects. In part 1, the subjects received a single dose of ilaprazole 10 mg in period 1 and clarithromycin 500 mg and amoxicillin 1000 mg twice daily for 6 days in period 2. In part 2, the subjects received clarithromycin 500 mg and amoxicillin 1000 mg once in period 1 and ilaprazole 10 mg twice daily for 6 days in period 2. In both sequences, the three drugs were coadministrated once on day 5 in period 2. Pharmacokinetic evaluations of ilaprazole (part 1), and clarithromycin and amoxicillin (part 2) were conducted., Results: Twenty-eight subjects completed the study. For ilaprazole, the peak concentration (C max ) slightly decreased from 479 (ilaprazole alone) to 446 ng/mL (triple therapy) [Geometric least square mean ratio (90% confidence interval), 0.93 (0.70-1.22)]. The area under the concentration-time curve from 0 h to the last measurable concentration (AUC last ) slightly increased from 3301 to 3538 μg·h/mL [1.07 (0.85-1.35)]. For clarithromycin, the C max slightly decreased from 1.87 to 1.72 μg/mL [0.90 (0.70-1.15)], and AUC last slightly increased from 14.6 to 16.5 μg·h/mL [1.09 (0.87-1.37)]. For amoxicillin, the C max slightly decreased from 9.37 to 8.14 μg/mL [0.86 (0.74-1.01)], and AUC last slightly decreased from 27.9 to 26.7 μg·h/mL [0.98 (0.83-1.16)]. These changes in the PK parameters of each drug were not statistically significant., Conclusions: The coadministration of ilaprazole, clarithromycin, and amoxicillin was tolerable and did not cause a significant PK drug interaction. Thus, a triple therapy regimen comprising ilaprazole, clarithromycin, and amoxicillin may be an option for the eradication of H. pylori. Clinicaltrials.gov number: NCT02998437.

Purpose: This drug-interaction study evaluated the effect of omeprazole, a proton-pump inhibitor, on ibrutinib's pharmacokinetics (PK) in healthy participants., Methods: This open-label, sequential-design study included 20 healthy adults aged 18-55 years. Ibrutinib (560 mg, single dose) was administered after an overnight fast alone on day 1 and with omeprazole on day 7. Omeprazole (40 mg) alone was administered on days 3-6, 1 h before breakfast; and after an overnight fast on day 7, followed by ibrutinib 2 h later. Blood was sampled on days 1 and 7 for up to 48 h postdose, and the standard PK parameters for ibrutinib and PCI-45227 were summarized using descriptive statistics. The effect of omeprazole on ibrutinib's PK was determined by assessing geometric mean ratios (GMRs) and 90% CIs. Mechanistic modeling was performed using the BTK-receptor occupancy (RO) model., Results: AUC 48h and AUC last of ibrutinib plus omeprazole versus ibrutinib alone showed a modest decrease (GMR [90% CI] 98.3% [83.1-116.3] and 92.5% [77.8-109.9], respectively); C max decreased by 62.5% (GMR [90% CI] 37.5% [26.4-53.4]), with delayed t max (1-2 h) and terminal half-life unaffected. Mean AUC for PCI-45227 (primary metabolite) was ~ 20% lower with ibrutinib plus omeprazole versus ibrutinib alone. Model predictions showed no impact of decreased C max on BTK target engagement. No new safety signals were identified with the use of ibrutinib in this study., Conclusions: The decrease in C max without a corresponding decrease in AUC by omeprazole was not clinically relevant for ibrutinib's bioavailability. No dose adjustments are recommended during ibrutinib's co-administration with omeprazole or other pH-altering agents.

This study involved the development, validation and application of a three-phase hollow-fiber liquid-phase microextraction (HF-LPME) and liquid chromatography with diode array detection (LC-DAD) method for the simultaneous determination of the proton pump inhibitor (PPI) drugs omeprazole, pantoprazole and lansoprazole in human plasma. The evaluation of the HF-LPME parameters was crucial for the determination of the drugs and the conditions selected were: 1-octanol as solvent; phosphate buffer at pH 5 as donor phase; borate buffer at pH 10 as acceptor phase; extraction time of 15 min; stirring at 750 rpm and NaCl was added at 5% (w/v). Validation of the method according to US-FDA recommendations showed a good linear range (0.2-2.0 μg/mL) for all analytes, with a determination coefficient >0.9910. Precision was evaluated using intra- and inter-day assays, which showed relative standard deviations (RSD), <15% for all concentrations, with a limit of quantification (LOQ) of 0.2 μg/mL. Accuracy was also assessed at these concentration levels and was in the range from 80 to 130%. Finally, the sensitive, selective and reproducible HF-LPME/LC-DAD developed method was successfully applied to human plasma samples from patients undergoing therapy with the PPI drugs.

Aims: Although substantial progress has been made in understanding of ontogeny of drug metabolism, there is still a gap of knowledge in developmental pharmacogenetics in neonates. We hypothesized that both age and pharmacogenetics might explain the developmental pattern of CYP2C19. We conducted a population pharmacokinetic-pharmacogenetic study to quantify the developmental pharmacogenetics of CYP2C19 in neonates and young infants using omeprazole as a probe drug., Methods: Pharmacokinetic samples were collected from 51 Caucasian neonates and young infants, who were receiving omeprazole treatment. Population pharmacokinetic-pharmacogenetic analysis of omeprazole and its metabolites was performed using NONMEM., Results: Data fitted a one-compartment parent and metabolite model with first-order absorption and elimination. CYP2C19 and CYP3A4 are predominantly involved in the metabolism of omeprazole despite their relatively low activities compared to adults. The clearance of omeprazole converted to 5-hydroxy-omeprazole (CL OMZ-M1 ) increases with postnatal age. In CYP2C19 poor and intermediate metabolizers, model-predicted CL OMZ-M1 are 12.5% (5-95% percentile: 3-14.9%) and 44.9% (5-95% percentile: 29.9-72.6%) of the value in extensive/ultrarapid metabolizer, respectively. Model-predicted absorption rate constant of omeprazole is 6.93 (5-95% percentile: 3.01-14.61) times higher in ABCB1 homozygous mutant patients, 1.86 (5-95% percentile: 0.86-3.47) times higher in ABCB1 heterozygous patients than that in ABCB1 homozygous wild-type patients., Conclusions: Developmental pharmacogenetics of CYP2C19 was quantitatively described in neonates and young infants using omeprazole as a probe drug. Our findings emphasize the importance of semiphysiological developmental pharmacokinetic modelling approach when evaluating developmental pharmacogenetics of drugs with multiple routes of biotransformation., (© 2018 The British Pharmacological Society.)

The pharmacokinetics (PK) and pharmacodynamics (PD) of proton pump inhibitors differ among cytochrome P450 (CYP) 2C19 genotypes. Therefore, we developed azeloprazole sodium (Z-215), a novel proton pump inhibitor, whose metabolism is not affected by CYP2C19 activity in vitro. However, the PK and PD of azeloprazole sodium have not been evaluated in Japanese subjects. We conducted an open-label, crossover study in healthy Japanese male volunteers to evaluate the plasma concentration and intragastric pH with respect to CYP2C19 genotype after repeated administration of 10, 20, and 40 mg azeloprazole sodium and 10 and 20 mg rabeprazole sodium (rabeprazole). The plasma concentration profile of azeloprazole sodium was similar among genotypes, whereas that of rabeprazole differed. The 24-hour intragastric pH ≥ 4 holding time ratio (pH ≥ 4 HTR) of azeloprazole sodium was similar among genotypes. The pH ≥ 4 HTR was 52.5%-60.3%, 55.1%-65.8%, and 69.4%-77.1% after administration of 10, 20, and 40 mg azeloprazole sodium, respectively, and 59.2%-72.3% and 64.4%-91.2% after administration of 10 and 20 mg rabeprazole, respectively, on the fifth day of dosing. The maximum plasma concentration (C max ), area under the plasma concentration-time curve (AUC), and pH ≥ 4 HTR of azeloprazole sodium were proportional to dose. The C max , AUC, and pH ≥ 4 HTR on day 5 were slightly higher following administration of 20 mg azeloprazole sodium before comparison with after a meal. No serious adverse events were observed. These results suggest that azeloprazole sodium is useful for treating gastroesophageal reflux disease in all CYP2C19 genotypes., (© 2017, The American College of Clinical Pharmacology.)

A new validated bio-analytical LC-MS/MS method was developed for the simultaneous extraction and determination of four proton pump inhibitors: esomeprazole, lansoprazole, pantoprazole and rabeprazole in human plasma using escitalopram as an internal standard. The proteins in plasma samples were precipitated using acetonitrile for the extraction of analytes which is a simple economic method. The separation was accomplished using a mobile phase composed of 10 mM ammonium formate: acetonitrile: methanol (20:40:40% v/v) at a flow rate of 0.8 mL/min in isocratic mode on a reversed phase C18 INERTSIL ODS-3 (5 μm, 150 × 4.6 mm) and column temperature of 40 °C. Positive mode electrospray ionization source was used prior to multiple reaction monitoring (MRM) detection using parent and daughter ions: m/z 346.2 → 198.1 for esomeprazole, m/z 370.1 → 252 for lansoprazole, m/z 384.2 → 200.2 for pantoprazole, m/z 360.1 → 242.1 for rabeprazole and m/z 325.2 → 109 for escitalopram. The calibration curves were constructed, and the method was linear in the range of 20-5000 ng/mL applying weighted (1/X 2 ) linear regression coefficient for all drugs. The method was fully validated following US-FDA and EMA guidelines., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: To demonstrate bioequivalence between two esomeprazole formulations under fasted and fed conditions., Materials: Esomeprazole 20 mg multiunit pellet system (test; MUPS) tablets and over-the-counter esomeprazole 20 mg banded capsules (reference)., Materials and Methods: This open-label, randomized, 6-period crossover study assigned healthy males and females to receive single doses of each study drug under fasted or fed conditions. The primary pharmacokinetic endpoints were esomeprazole area under the concentration-time curve from time zero to infinity (AUC inf ) and maximum observed concentration (C max ). For endpoints with high within-subject standard deviations of the reference product (S wr ≥ 0.294), a reference scaled average bioequivalence (RSAB) approach was used. For endpoints not highly variable (S wr < 0.294), an unscaled approach was used. In the RSAB, bioequivalence was defined as the 95% criteria bound (CB) ≤ 0 and geometric mean ratios (GMRs) within 0.80, 1.25. For the unscaled approach, bioequivalence was defined as 90% confidence intervals (CIs) of the GMR being within 80%, 125%., Results: 60 subjects were randomized, and 46 subjects (76.7%) completed all study periods. For esomeprazole AUC inf , the variability of the reference product was low (S wr  = 0.202), so the unscaled approach was used. The GMR (90% CI) was 0.948 (0.890 - 1.010), indicating bioequivalence. For the comparison of esomeprazole C max , the variability of the reference product was high (S wr = 0.304), so the RSAB approach was used. The GMR (95% CB) was 1.009 (-0.050), indicating bioequivalence., Conclusion: Esomeprazole 20 mg MUPS tablets and banded capsules were found to be bioequivalent based on the AUC inf and C max in the fasted state.
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Only limited data are available regarding the treatment of critically ill patients with clopidogrel. This trial investigated the effects and the drug concentrations of the cytochrome P450 (CYP450) activated prodrug clopidogrel (n = 43) and the half-life of the similarly metabolized pantoprazole (n = 16) in critically ill patients. ADP-induced aggregometry in whole blood classified 74% (95% confidence intervals 59-87%) of critically ill patients as poor responders (n = 43), and 65% (49-79%) responded poorly according to the vasodilator-stimulated phosphoprotein phosphorylation (VASP-P) assay. Although the plasma levels of clopidogrel active metabolite normally exceed the inactive prodrug ∼30-fold, the parent drug levels even exceeded those of the metabolite 2-fold in critically ill patients. The half-life of pantoprazole was several-fold longer in these patients compared with reference populations. The inverse ratio of prodrug/active metabolite indicates insufficient metabolization of clopidogrel, which is independently confirmed by the ∼5-fold increase in half-life of pantoprazole. Thus, high-risk patients may benefit from treatment with alternative platelet inhibitors., (© 2017 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

The aim of this research was to compare three strategies for enhancing the solubility of poorly water-soluble revaprazan hydrochloride: solid dispersion, solid SNEDDS and inclusion compound. The influence of polymers, surfactants and oils on the drug solubility was assessed, and via the chosen carriers, the three types of formulations were prepared utilising spray drying technique. Their physicochemical properties, solubility, dissolution and pharmacokinetics in rats were performed compared with revaprazan powder. Among the liquid SNEDDS formulations assessed, the compositions of revaprazan, peceol, Tween 80 and Labrasol (10:15:55:30, weight ratio) provided the smallest emulsion size. Moreover, this liquid SNEDDS and dextran were suspended/dissolved in distilled water, and spray-dried, producing an optimal revaprazan-loaded solid SNEDDS. The appropriate solid dispersion and inclusion compound were composed of revaprazan, hydroxypropylmethylcellulose and cremophor A25 (5:1.4:5.6) and drug and hydroxyl-β-cyclodextrin (2.5:8.77), respectively. The crystalline drug was converted to an amorphous state in all formulations. In the solid dispersion, the drug was attached to the hydrophilic carrier. The solid SNEDDS and inclusion compound contained aggregate microspheres and separate microspheres, respectively. All formulations significantly increased the drug solubility, dissolution, plasma concentration and AUC compared with revaprazan powder. These properties were ranked in the order solid dispersion ≥ solid SNEDDS > inclusion compound. Particularly, the solid dispersion improved about 9500-fold drug solubility and 10-fold oral bioavailability. Thus, the improved properties were considerably dependent upon these techniques, although all of the techniques employed similar mechanisms. Among the strategies checked, the solid dispersion system would be recommended as an oral revaprazan-loaded pharmaceutical product., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Omeprazole (OMP) a proton pump inhibitor is widely used to suppress gastric acid secretions of parietal cells of stomach and metabolized predominantly by CYP2C19. The objective of the present study was to investigate the pharmacokinetics and dosage regimen of OMP, after its single oral administration in eight healthy adult female subjects. Blood samples were collected at different time intervals after oral administration and their pH was measured. Plasma concentration of OMP was determined by high performance liquid chromatography (HPLC) system equipped with UV-visible Detector. The concentration versus time data was used to compute the pharmacokinetic parameters with the help of computer software programme MW/PHRAM APO version 3.02.Peak plasma concentration was (C max ) 0.38±0.04 μg/ml achieved at 2.07±0.22 hrs. The elimination half-life (t 1/2 β) was1.82 ± 0.42 hrs. Volume of distribution (Vd) in the present study was 0.40 ± 0.07 l/kg with total body clearance (Cl B ) 0.19 ± 0.02 l/hr/kg and area under the curve (AUC) 1.89 ± 0.23 μg.hr/ml.The pharmacokinetic properties which are different from the literature after oral administration of 20 mg OMP in eight healthy female volunteers may be due to the variations of environment and genetic variation between Pakistan and drug manufacturing of foreign countries.

The present study focused to develop rapid, accurate and sensitive reversed-phase high pressure liquid chromatography method for the quantification of esomeprazole (ESO) magnesium in rabbit plasma. Chromatographic separation was achieved isocratically on a reversed-phase C,, column using simple mobile phase consisting of of methanol : acetonitrile: 0.05 M phosphate buffer, pH 7 adjusted with potassium hydroxide (45 : 10 : 45, v/v/v) at a flow rate of 1.0 mL/min and UV detection at 302 nm. The method was validated for system suitability, linearity, precision, accuracy, stability, robustness, LOD and LOQ. The described method stated good linearity over the range of 0.01 to 2.5 pg/mL (r = 0.999). The extraction recovery of esomeprazole was more than 95.3%. The method was precise with relative standard deviation < 1% with more than 90% accuracy and limit of quantification 0.0309 μg/mL. The freeze thaw stability studies indicated that the rabbit plasma samples containing esomeprazole could be stored in freezer at -20⁰C and handled under normal laboratory conditions without significant loss of drug. In conclusion, the developed method is simple, cost effective and reproducible, with improved sensitivity and running time of analysis.

Omeprazole is a widely prescribed proton pump inhibitor to treat various gastric acid hyper secretion disorders. The present study was designed to evaluate the renal clearance and urinary excretion of omeprazole in eight healthy female volunteers to increase the understanding of the contributing factors such as demographics variability in the renal clearance and urinary excretion of omeprazole under indigenous conditions. The urine and blood samples were collected 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours after oral administration of enteric coated omeprazole (20 mg) and drug concentration in the samples was determined by High Performance Liquid Chromatography (HPLC) with C18 column and UV detector. Urinary excretion and renal clearance of omeprazole was calculated and data was statistically analyzed by using regression/correlation technique. Endogenous creatinine was also measured by reagent kit available in the market. The results indicate that mean diuresis was 0.0172±0.0029 ml/min/kg. While the mean values of renal clearance of creatinine and omeprazole were 1.315±0.103 and 0.066±0.0042 ml/min. kg, respectively. Whereas, clearance ratio was 0.055±0.007 which indicates back diffusion. The cumulative percentage of dose excreted was 6.71±0.358. A significant (p<0.05) negative correlation (r= -0.457) between clearance ratio and urine pH of omeprazole reflecting glomerular filtration reabsorption of drug at kidney tubular level while significant (p<0.05) negative correlation (r= -0.681) between clearance ratio and plasma concentration of omeprazole indicates the involvement of active tubular secretion of drug. It can be concluded that during glomerular filtration, omeprazole diffuse back/reabsorption. Therefore, Urinary excretion of omeprazole in indigenous healthy female subjects was observed to be lower than given in the literature values.

Pantoprazole is a proton pump inhibitor that is commonly used in the treatment of peptic ulcer disease (PUD) and metabolized by cytochrome P450 (CYP) enzymes CYP2C19 and CYP3A4. Pantoprazole is a substrate for multi-drug resistance protein 1 (MDR1). Single nucleotide polymorphisms (SNPs) in CYP2C19, CYP3A4 and MDR1 affect enzyme activity or gene expression of proteins and may alter plasma pantoprazole concentrations and treatment success in PUD. In this study, we aimed to investigate the association between genetic polymorphisms in CYP2C19, CYP3A4 and MDR1 and pharmacokinetics of pantoprazole and therapeutic outcome in patients with either Helicobacter pylori-associated [H.P.(+)]-PUD or [H.P.(+)]-gastritis. The plasma pantoprazole concentrations were determined by using an HPLC method at the third hour after a 40-mg tablet of pantoprazole administration in 194 newly diagnosed patients with either [H.P.(+)]-PUD or [H.P.(+)]-gastritis. Genotyping was performed by using PCR-RFLP and DNA sequencing. Among patients appearing for follow-up examination (n = 105), the eradication rate for H. pylori was 82.8% (n = 87). The median pantoprazole plasma concentrations in poor metabolizers (PM), rapid metabolizers (RM) and ultrarapid metabolizers (URM) were 2.07, 1.69 and 1.28 μg/ml, respectively (p = 0.04). CYP3A4*1G and *22 polymorphisms did not affect plasma pantoprazole concentrations and H. pylori eradication rate. The MDR1 genetic polymorphisms did not affect plasma pantoprazole concentrations. MDR1 3435CC-2677GG-1236CC haplotype carriers had lower H. pylori eradication rate (60%) than the remaining subjects (84.9%) while the difference was not statistically significant (p = 0.07). In conclusion, while CYP2C19 genetic polymorphisms significantly affected plasma pantoprazole concentrations, polymorphisms of CYP2C19, CYP3A4 and MDR1 did not affect H. pylori eradication rates., (© 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Aspirin and P2Y 12 receptor antagonists are widely used across the spectrum of cardiovascular diseases. Upper gastrointestinal complications, including ulcer and bleeding, are relatively common during antiplatelet treatment and, therefore, concomitant proton pump inhibitor (PPI) treatment is often prescribed.PPIs provide gastroprotection by changing the intragastric milieu, essentially by raising intragastric pH. In recent years, it has been heavily discussed whether PPIs may reduce the cardiovascular protection by aspirin and, even more so, clopidogrel. Pharmacodynamic and pharmacokinetic studies suggested an interaction between PPIs and clopidogrel, and subsequent clinical studies were conducted to evaluate the clinical impact of this interaction. More recently, it was reported that PPIs may also attenuate the antiplatelet effect of aspirin. This may be clinically important, because a fixed combination of aspirin and a PPI (esomeprazole) has recently been approved and because aspirin is the most widely used drug in patients with cardiovascular disease. The antiplatelet effect of the new P2Y 12 receptor antagonists, ticagrelor and prasugrel, seems less influenced by PPI co-treatment.Given the large number of patients treated with antithrombotic drugs and PPIs, even a minor reduction of platelet inhibition potentially carries considerable clinical impact. The present book chapter summarizes the evidence regarding the widespread use of platelet inhibitors and PPIs in combination. Moreover, it outlines current evidence supporting or opposing drug interactions between these drugs and discusses clinical implications.

Objective: We aimed to identify the best method of omeprazole (OME) application with respect to intragastric pH, cytochrome P450 2C19 (CYP2C19) genotype and phenotype., Methods: The patients with non-variceal upper gastrointestinal bleeding (NVUGIB) were prospectively enrolled. After the achievement of endoscopic hemostasis, the patients were randomized to 40-mg intravenous (i.v.) OME bolus injection every 12 h or 8-mg/h continuous i.v. infusion for 72 h after an 80-mg i.v. OME bolus administration. The intragastric pH was recorded for 72 h. The CYP2C19 variant alleles (*2, *3, *17) were analyzed and the serum concentrations of OME and 5-hydroxyomeprazole (5-OH OME) were determined., Results: Altogether 41 Caucasians (18 in the OME infusion [OI] group and 23 in the OME bolus [OB] group) were analyzed. The median percentage of time with an intragastric pH > 4.0 was higher in the infusion group than in the OB group over 48 h (100% vs 96.6%, P = 0.009) and 72 h (100% vs 87.6%, P = 0.006), and that at an intragastric pH >6.0 was higher in the OI group than the OB group over 72 h (97.9% vs 63.5%, P = 0.04). Helicobacter pylori infection was correlated with the fastest increase in intragastric pH, especially in the OI group. In both groups, CYP2C19 genotypes (*1/*1, *1/*17, *17/*17) had no essential effect on intragastric pH., Conclusions: In patients with NVUGIB, OME i.v. bolus followed by continuous infusion is more effective than OME i.v. bolus every 12 h in maintaining higher intragastric pH, regardless of CYP2C19 genetic polymorphisms. H. pylori infection accelerates the initial elevation of intragastric pH., (© 2016 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

The advances in pharmaceutical development and drug discovery impose the availability of reliable high-throughput screening methods for the rapid evaluation of drug metabolism and pharmacokinetic (PK) in biological samples. Here, a desorption electrospray mass spectrometry (DESI-MS) method has been developed and validated for the PK profiling of esomeprazole and its metabolites (5-hydroxyomeprazole and omeprazole sulfone) in rat plasma. Rats were treated with an esomeprazole solution (2.5 mg/mL) for endovenous administration and the analyte levels were profiled over 2 h after liquid-liquid extraction from plasma. MS and tandem mass spectrometry (MS/MS) experiments were performed by using a DESI-LTQ-Orbitrap XL instrument and an on-spot fixed time analysis on PMMA surfaces. Validation was performed for the esomeprazole. The DESI-MS/MS method exhibited for the esomepazole excellent sensitivity (limit of detection (LOD)=60 ng/mL), linearity (0.2-20 µg/mL concentration range; y=23848(±361)X, n=15; r(2) =0.987) and precision (RSD<9%) by using an internal standard method. The PK results were discussed in terms of Area Under the Curve, Cmax and Tmax . Data reliability was demonstrated by comparison with a liquid chromatography-tandem mass spectrometry method (p>0.05). The data achieved demonstrated that the DESI-MS method is suitable for sensitive and fast profiling of a drug and its metabolites at the therapeutic concentration levels., (Copyright © 2015 John Wiley & Sons, Ltd.)

Background: Pantoprazole is a proton pump inhibitor drug mainly used for treating peptic diseases. Adverse effects of pantoprazole in the occasional central nervous system (CNS) include headache, vertigo and sleep disturbances. Data in rats suggest that proton pumps are expressed in the inner ear and in the epithelium of the choroid plexus, which would be a potential target to mediate such proton pump inhibitor effects., Methods: To assess the distribution of pantoprazole into the human CNS despite its low lipophilicity (log p = 0.5), we quantified pantoprazole concentrations by liquid chromatography/tandem mass spectrometry in serum and cerebrospinal fluid retain samples withdrawn simultaneously. Twenty-six sample pairs were obtained from 23 neurological patients with therapeutic administration of pantoprazole prior to sampling., Results: Median (interquartile range) serum concentration of total pantoprazole was 142 ng/ml (30.8-622). Cerebrospinal fluid concentration of total pantoprazole was 2.79 ng/ml (1.59-7.3) and reached 2.0% (1.0-4.5%) of simultaneous serum concentrations., Conclusion: This value corresponds to the unbound fraction of pantoprazole in serum reported previously and indicates that pantoprazole CNS concentrations are high enough to exert some effects on possible CNS targets., (© 2016 S. Karger AG, Basel.)

The combination of aspirin and the thienopyridine clopidogrel is a cornerstone in the prevention of atherothrombotic events. These two agents act in concert to ameliorate the prothrombotic processes stimulated by plaque rupture and vessel injury complicating cardiovascular disease. Guidelines recommend the use of clopidogrel in patients with acute coronary syndromes and in those undergoing percutaneous coronary intervention, and the drug remains the most utilized P2Y12 receptor inhibitor despite the fact that newer antiplatelet agents are now available. In recent years, numerous studies have shown inconsistency in the efficacy of clopidogrel to prevent atherothrombotic events. Studies of platelet function testing have shown variability in the response to clopidogrel. One of the major reason for this phenomenon lies in the interaction between clopidogrel and other drugs that may affect clopidogrel absorption, metabolism, and ultimately its antiplatelet action. Importantly, these drug-drug interactions have prognostic implications, since patients with high on-treatment platelet reactivity associated with reduced clopidogrel metabolism have an increased risk of ischemia. Previous systematic reviews have focused on drug-drug interactions between clopidogrel and specific pharmacologic classes, such as proton pump inhibitors, calcium channel blockers, and statins. However, more recent pieces of scientific evidence show that clopidogrel may also interact with newer drugs that are now available for the treatment of cardiovascular patients. Accordingly, the aim of this review is to highlight and discuss recent data on drug-drug interactions between clopidogrel and third-generation proton pump inhibitors, pantoprazole and lansoprazole, statins, pitavastatin, and antianginal drug, ranolazine., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: We aimed to compare the plasma pantoprazole level (PPL) between patients with type 2 diabetes mellitus and non-diabetic patients during Helicobacter pylori (H. pylori) eradication treatment and to explore the role of PPL in predicting the treatment success rates., Methods: This study included 40 diabetic and 40 non-diabetic treatment-naive H. pylori-infected patients. Bismuth-based standard quadruple treatment for H. pylori eradication was used for 14 days in both groups. PPL was measured using the square-wave voltammetry method., Results: H. pylori eradication rate (60.0% vs 87.5%, P = 0.005) and PPL (0.25 ± 0.03 μg/mL vs 0.34 ± 0.03 μg/mL, P < 0.001) was significantly lower in the diabetic group compared with the controls. Patients with treatment failure had lower PPL than those with successful treatment (P < 0.001). The receiver operating characteristics curve demonstrated that PPL had a significant predictive value for the outcome of H. pylori eradication., Conclusion: Type 2 diabetic patients had lower PPL than the non-diabetic controls, which led to their lower H. pylori eradication rates., (© 2015 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.)

A specific ultra-performance liquid chromatography tandem mass spectrometry method is described for the simultaneous determination of bupropion, metroprolol, midazolam, phenacetin, omeprazole and tolbutamide in rat plasma with diazepam as internal standard, which are the six probe drugs of the six cytochrome P450 isoforms CYP2B6, CYP2D6, CYP3A4, CYP1A2, CYP2C19 and CYP2C9. Plasma samples were protein precipitated with acetonitrile. The chromatographic separation was achieved using a UPLC® BEH C18 column (2.1 × 100 mm, 1.7 µm). The mobile phase consisted of acetonitrile and water (containing 0.1% formic acid) with gradient elution. The triple quadrupole mass spectrometric detection was operated by multiple reaction monitoring in positive electrospray ionization. The precisions were <13%, and the accuracy ranged from 93.3 to 110.4%. The extraction efficiency was >90.5%, and the matrix effects ranged from 84.3 to 114.2%. The calibration curves in plasma were linear in the range of 2-2000 ng/mL, with correlation coefficient (r(2) ) >0.995. The method was successfully applied to pharmacokinetic studies of the six probe drugs of the six CYP450 isoforms and used to evaluate the effects of erlotinib on the activities of CYP2B6, CYP2D6, CYP3A4, CYP1A2, CYP2C19 and CYP2C9 in rats. Erlotinib may inhibit the activity of CYP2B6 and CYP3A4, and may induce CYP2C9 of rats., (Copyright © 2015 John Wiley & Sons, Ltd.)

Background: HCP1004 is a newly developed fixed-dose combination of naproxen (500 mg) and esomeprazole strontium (20 mg) that is used in the treatment of rheumatic diseases and can reduce the risk of nonsteroidal anti-inflammatory drug-associated ulcers. The aim of this study was to evaluate the pharmacokinetics (PK) and safety of HCP1004 compared to VIMOVO(®) (a marketed fixed-dose combination of naproxen and esomeprazole magnesium)., Subjects and Methods: An open-label, randomized, two-treatment, two-sequence crossover, single-dose clinical study was conducted in 70 healthy volunteers. In each period, a reference (VIMOVO(®)) or test (HCP1004) drug was administered orally, and serial blood samples for PK analysis were collected up to 72 hours after dosing. To evaluate the PK profiles, the maximum plasma concentration (Cmax) and the area under the concentration-time curve from 0 to the last measurable time (AUC0-t) were estimated using a noncompartmental method. Safety profiles were evaluated throughout the study., Results: Sixty-six of the 70 subjects completed the study. The Cmax (mean ± standard deviation) and AUC0-t (mean ± standard deviation) for naproxen in HCP1004 were 61.67 ± 15.16 µg/mL and 1,206.52 ± 166.46 h · µg/mL, respectively; in VIMOVO(®); these values were 61.85 ± 14.54 µg/mL and 1,211.44 ± 170.01 h · µg/mL, respectively. The Cmax and AUC0-t for esomeprazole in HCP1004 were 658.21 ± 510.91 ng/mL and 1,109.11 ± 1,111.59 h · ng/mL, respectively; for VIMOVO(®), these values were 595.09 ± 364.23 ng/mL and 1,015.12 ± 952.98 h · ng/mL, respectively. The geometric mean ratios and 90% confidence intervals (CIs) (HCP1004 to VIMOVO(®)) of the Cmax and AUC0-t of naproxen were 0.99 (0.94-1.06) and 1.00 (0.98-1.01), respectively. For esomeprazole, the geometric mean ratios (90% CI) for the Cmax and AUC0-t were 0.99 (0.82-1.18) and 1.04 (0.91-1.18), respectively. The overall results of the safety assessment showed no clinically significant issues for either treatment., Conclusion: The PK of HCP1004 500/20 mg was comparable to that of VIMOVO(®) 500/20 mg for both naproxen and esomeprazole after a single oral dose. Both drugs were well-tolerated without any safety issues.

Purpose: The purpose of this study is to evaluate the ethnicity-specific population models in the SimCYP Simulator® for prediction of omeprazole clearance with attention to differences in the CYP2C19 metabolic pathway., Methods: The SimCYP® models incorporating Caucasian, Chinese, and Japanese population-specific demographic, physiological, and enzyme data were applied to simulate omeprazole pharmacokinetics. Published pharmacokinetic data of omeprazole after intravenous or oral administration in Caucasian, Chinese, and Japanese were used for the evaluation., Results: Following oral administration, the ratio of the predicted to observed geometric mean of omeprazole clearance in Caucasian extensive metabolizers (EMs) was 0.88. The ratios in Chinese EMs were 1.16 and 0.99 after intravenous and oral administration, respectively. The ratios in Japanese EMs were 0.88 and 0.71 after intravenous and oral administration, respectively. Significant differences (2-fold) in the observed oral clearance of omeprazole were identified between Caucasian and Asian (Chinese and Japanese) EMs while the observed oral and intravenous clearances of omeprazole were similar between Chinese and Japanese EMs. Physiologically based pharmacokinetics (PBPK) models within SimCYP accurately predicted the difference in the observed oral clearance between Caucasian and Chinese EMs but overpredicted the difference between Caucasians and Japanese EMs due to under-prediction of oral clearance in Japanese EMs., Conclusions: The PBPK model within SimCYP adequately predicted omeprazole clearance in Caucasian, Chinese, and Japanese EMs and the 2-fold differences in clearance of omeprazole between Caucasian and Asian EMs. This may lead to early identification of ethnic sensitivity in clearance and the need for different dosing regimens in a specific ethnic group for substrates of CYP2C19 which can support the rational design of bridging clinical trials.

Omeprazole (OMP) is effective in the treatment of gastric hyperacidity and is metabolized by CYP2C19 and CYP3A4. These enzymes are modulated by estrogen and progesterone which regulate the menstrual cycle. The variations in the pharmacokinetics (PK) of many drugs like amphetamine, benzodiazepines and caffeine have been reported during menstrual cycle. In present study, the PK of the omeprazole and its metabolites was investigated during various phases of the menstrual cycle. A single oral dose, open-label, non-controlled, pharmacokinetic study of omeprazole was conducted in healthy young/premenopausal females (n = 16). The PK of omeprazole, 5-hydroxy-omeprazole and omeprazole sulphone was evaluated in three phases of menstrual cycle. The blood samples were analyzed using reversed-phase HPLC coupled with UV detector and the PK data were evaluated. The activities of CYP2C19 and CYP3A4 were determined as AUC(OH-OMP)/AUC(OMP) and AUC(OMP-SUL)/AUC(OMP), respectively. Omeprazole showed significantly (p < 0.05) higher [Formula: see text] and CL/F in follicular and menstrual phases, respectively. The [Formula: see text] of 5-hydroxy omeprazole was also significantly (p < 0.05) higher in follicular phase. The metabolic ratios (MR) of 5-hydroxy omeprazole and omeprazole sulphone were lower in follicular phase compared with the luteal phase. The present study suggests that high estrogen levels of follicular phase may result in increased absorption of omeprazole. The lower MR for 5-hydroxy omeprazole and omeprazole sulphone in follicular phase as compared to luteal phase suggests that metabolism of omeprazole is low in follicular phase as compared to luteal phase, which is progesterone-dominant phase. However, the clinical significance for these findings needs to be determined.

Background: Polymorphism of CYP2C19 gene is one of the important factors in pharmacokinetics of CYP2C19 substrates. Omeprazole is a proton pump inhibitor which is mainly metabolized by cytochrome P450 2C19 (CYP2C19). The aim of present study was to assess omeprazole hydroxylation index as a measure of CYP2C19 activity considering new variant allele (CYP2C19*17) in Iranian population and also to see if this activity is sex dependent., Methods: One hundred and eighty healthy unrelated Iranian individuals attended in this study. Blood samples for genotyping and phenotyping were collected 3 hours after administration of 20 mg omeprazole orally. Genotyping of 2C19 variant alleles *2, *3 and *17 was performed by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and semi-nested PCR methods. Plasma concentrations of omeprazole and hydroxyomeprazole were determined by high performance liquid chromatography (HPLC) technique and hydxroxylation index (HI) (omeprazole/ hydroxyomeprazole) was calculated., Results: The CYP2C19*17 was the most common variant allele in the studied population (21.6%). Genotype frequencies of CYP2C19*17*17, *1*17, and *2*17 were 5.5%, 28.8% and 3.3% respectively. The lowest and the highest median omeprazole HI was observed in *17*17 and *2*2 genotypes respectively (0.36 vs. 13.09). The median HI of omeprazole in subjects homozygous for CYP2C19*1 was 2.16-fold higher than individuals homozygous for CYP2C19*17 (P < 0.001) and the median HI of CYP2C19*1*17 genotype was 1.98-fold higher than CYP2C19 *17*17 subjects (P < 0.001). However, subjects with CYP2C19*2*17 (median HI: 1.74) and CYP2C19*1*2 (median HI: 1.98) genotypes and also CYP2C19*1*17 (median HI: 0.71) and CYP2C19*1*1 (mean HI: 0.78) did not show any significantly different enzyme activity. In addition, no statistically significant difference was found between women and men in distribution of CYP2C19 genotypes. Furthermore, the hydroxylation index of Omeprazole was not different between women and men in the studied population., Conclusion: Our data point out the importance of CYP2C19*2 and CYP2C19*17 variant alleles in metabolism of omeprazole and therefore CYP2C19 activity. Regarding the high frequency of CYP2C19*17 in Iranian population, the importance of this new variant allele in metabolism of CYP2C19 substrates shall be considered.

Background: The novel iron-based phosphate binder sucroferric oxyhydroxide is being investigated for the treatment of hyperphosphatemia. Patients with chronic kidney disease often have multiple comorbidities that may necessitate the daily use of several types of medication. Therefore, the potential pharmacokinetic drug-drug interactions between sucroferric oxyhydroxide and selected drugs commonly taken by dialysis patients were investigated., Methods: Five Phase I, single-center, open-label, randomized, three-period crossover studies in healthy volunteers investigated the effect of a single dose of sucroferric oxyhydroxide 1 g (based on iron content) on the pharmacokinetics of losartan 100 mg, furosemide 40 mg, omeprazole 40 mg, digoxin 0.5 mg and warfarin 10 mg. Pharmacokinetic parameters [including area under the plasma concentration-time curve (AUC) from time 0 extrapolated to infinite time (AUC0-∞) and from 0 to 24 h (AUC0-24)] for these drugs were determined: alone in the presence of food; with sucroferric oxyhydroxide in the presence of food; 2 h after food and sucroferric oxyhydroxide administration., Results: Systemic exposure based on AUC0-∞ for all drugs, and AUC0-24 for all drugs except omeprazole (for which AUC 0-8 h was measured), was unaffected to a clinically significant extent by the presence of sucroferric oxyhydroxide, irrespective of whether sucroferric oxyhydroxide was administered with the drug or 2 h earlier., Conclusions: There is a low risk of drug-drug interactions between sucroferric oxyhydroxide and losartan, furosemide, digoxin and warfarin. There is also a low risk of drug-drug interaction with omeprazole (based on AUC0-∞ values). Therefore, sucroferric oxyhydroxide may be administered concomitantly without the need to adjust the dosage regimens of these drugs.

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.

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.

Background: Ilaprazole, a proton pump inhibitor (PPI) currently in clinical use, may provide improved acid suppression vs. other PPIs., Aim: To compare the pharmacodynamic and pharmacokinetic profiles of ilaprazole and esomeprazole., Methods: A phase 1, randomised, open-label, single-centre, 4-period crossover study was conducted in 40 healthy volunteers. Ilaprazole 10, 20 or 40 mg or esomeprazole 40 mg was administered once daily for 5 days with ≥5-day washout intervals. Pharmacokinetic blood samples and intragastric pH measurements were collected at scheduled timepoints for 24 h after dosing on Days 1 and 5., Results: Esomeprazole 40 mg provided significantly better pH control during the initial hours (0-4 h) after a single dose, but ilaprazole (particularly 20 and 40 mg) provided significantly better pH control for the entire 24-h period and during evening and overnight hours after single and multiple doses. Increasing ilaprazole doses resulted in dose-proportional increases in peak plasma concentration and area under the plasma concentration vs. time curve following single and multiple doses. Ilaprazole was safe and generally well tolerated; an unexpectedly high incidence of allergic eye and skin reactions were observed but were not specific to any dosing regimen. Plasma gastrin concentrations did not increase proportionately with increasing ilaprazole dose., Conclusions: Ilaprazole provided significantly better pH control over 24 h and during evening and overnight hours compared with esomeprazole in healthy volunteers, which may translate to greater relief of night-time heartburn in the clinical setting for patients with gastric acid-related disorders., (© 2014 John Wiley & Sons Ltd.)

Background: Drug monitoring is a useful tool for obtaining detailed information about the disposition of a drug in an individual patient during chemotherapy. According to the international guidelines, the analytical assay for quantification of a compound in biological samples must be validated. Among a number of parameters, peak purity is an important requirement., Materials and Methods: We analyzed pharmacokinetics in patients who received chemotherapy with capecitabine and up to 10 various co-medications., Results: Out of seven investigated co-administered drugs, we found evidence that the proton pump inhibitor pantoprazole causes peak interferences with capecitabine during high-performance liquid chromatography analysis. Therefore quantification of capecitabine in plasma samples can be inaccurate., Conclusion: We recommend an altered time schedule for co-administered drugs or changing the mobile phase used in the assay., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

The objectives of the present work were to use blends of Eudragit L and hydroxypropyl methylcellulose acetate succinate (HPMCAS) as enteric film coatings for lansoprazole (LSP) pellets. The enteric-coated pellets were prepared with a fluid-bed coater. The influence of the blend ratio, type of plasticizer, plasticizer level, coating level, and curing conditions on gastric stability in vitro drug release and drug stability was evaluated. Furthermore, the bioavailability of the blend-coated pellets in beagle dogs was also performed. The blend-coated pellets exhibited significant improvement of gastric stability and drug stability compared to the pure polymer-coated pellets. Moreover, the AUC values of blend-coated pellets were greater than that of the pure polymer-coated pellets. It was concluded that the using blends of Eudragit L and HPMCAS as enteric film coatings for LSP pellets improved the drug stability and oral bioavailability.

The objective of this study was to assess the bioequivalence between the omeprazole laboratory based formulation and the commercial formulation, Zimor Rubio, Spain, considered as reference formulation. The experiment was carried out according to a 2-period, 2-sequence crossover design with a two week washout period. A validated high performance liquid chromatographic method was applied for in vivo experiments. It was observed that omeprazole contents were comparable in all formulations. To establish bioequivalence, 90% confidence intervals (CI) for the differences of total AUCs of the test and reference formulations were calculated. The 95% CI ratio of the AUC within 0.80 to 1.25 was considered as bioequivalent. The carryout effect was investigated prior to assessing the bioequivalence of the two formulations. The test formulation of omeprazole was found to be comparable with the reference formulation (Zimor) with regard to bioavailability.

The aim of the present study was to correlate in vitro properties of drug formulation to its in vivo performance, and to elucidate the deciding properties of oral absorption. Gastrointestinal simulation technology (GST) was used to simulate the in vivo plasma concentration-time curve and was implemented by GastroPlus™ software. Lansoprazole, a typical BCS class II drug, was chosen as a model drug. Firstly, physicochemical and pharmacokinetic parameters of lansoprazole were determined or collected from literature to construct the model. Validation of the developed model was performed by comparison of the predicted and the experimental plasma concentration data. We found that the predicted curve was in a good agreement with the experimental data. Then, parameter sensitivity analysis (PSA) was performed to find the key parameters of oral absorption. The absorption was particularly sensitive to dose, solubility and particle size for lansoprazole enteric-coated tablets. With a single dose of 30 mg and the solubility of 0.04 mg/ml, the absorption was complete. A good absorption could be achieved with lansoprazole particle radius down to about 25 μm. In summary, GST is a useful tool for profiling biopharmaceutical deciding properties of absorption of lansoprazole enteric-coated tablets and guiding the formulation optimization., (Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.)

Background: The CYP2C19*2 polymorphism is significantly associated with residual platelet reactivity (RPR) and maybe a major confounding factor in studies evaluating pharmacological interactions with clopidogrel., Objectives: We sought to evaluate the influence of a proton pump inhibitor (PPI), pantoprazole, indicated as relatively less influent than other PPIs, on the antiplatelet effect of clopidogrel, considering a stratification of the population for the presence of cytochrome 2C19*2 polymorphism., Methods: 105 patients with ST elevation myocardial infarction (STEMI), treated with percutaneous coronary angioplasty (PCI) and who received dual antiplatelet therapy, were randomized between pantoprazole (n=54) or ranitidine (n=51). RPR was evaluated by Platelet Function Analyzer-100 (PFA-100) with collagen-epinephrine (CEPI) and collagene-ADP (CADP) cartridges and by light transmitted aggregometry with 10 μM adenosin diphosphate (ADP) and 1mM arachidonic acid (AA), on 5 (T0) and 30 (T1) days after PCI., Results: Demographic, clinical and procedural data and the prevalence of CYP2C19*2 polymorphism were similar between the two groups. Not statistically differences were observed for CEPI-CT and for the maximal aggregation (MA) values with AA stimulus at both times. We observed a significant increase in MA values with ADP in PPI group at T0 (p=0.01) and T1 (p=0.03). At the multiple regression analysis PPI use remained significantly associated with ADP-MA both at T0 (p=0.05) and T1 (p=0.03)., Conclusions: This is the first documentation in a randomized trial, after correction for the bias of CYP2C19*2 polymorphism, that pantoprazole increases the ADP-MA in patients treated with dual antiplatelet therapy., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Omeprazole has (R)- and (S)-enantiomers, which exhibit different pharmacokinetics (PK) among patients with cytochrome P450 (CYP) 2C19 genotype groups. The aim of this study was to investigate whether the 1-point, 4-h postdose (R)-omeprazole hydroxylation index (HI) of racemic omeprazole reflects the three CYP2C19 genotype groups in Japanese individuals., Methods: Ninety healthy Japanese individuals were enrolled and classified into the three different CYP2C19 genotype groups: homozygous extensive metabolizers (hmEMs; n = 34), heterozygous EMs (htEMs; n = 44), and poor metabolizers (PMs; n = 12). Blood samples were drawn 4 h after the intake of an oral dose of omeprazole 40 mg, and plasma levels of omeprazole and its metabolites were analyzed by high-performance liquid chromatography (HPLC) using a chiral column., Results: Mean plasma concentrations of (R)- and (S)-omeprazole in PMs were significantly higher than those in hmEMs and htEMs, and similar results were obtained in the case of omeprazole sulfone. Additionally, there was a significant difference in plasma concentrations of (R)-5-hydroxyomeprazole among CYP2C19 genotype groups, whereas no significant differences were observed in that of (S)-5-hydroxyomeprazole. Similarly, (R)-omeprazole HI in hmEMs, htEMs, and PMs were 5.6, 3.1, and 0.3, respectively, which were significantly different, but no significant difference was present in the (S)-omeprazole HI., Conclusion: Our findings demonstrate that (R)-omeprazole HI correlated better with CYP2C19 genotype groups than racemic-omeprazole HI, and these results may be useful for classification among patients in CYP2C19 genotype groups prior to omeprazole treatment.

Purpose: This study was aimed to determine the impact of rabeprazole (RBRZ) on the antiplatelet efficacy of clopidogrel (CPG) in healthy Chinese volunteers, and further to predict the effect of CYP2C19 genetic polymorphism on the efficacy of rabeprazole and clopidogrel., Methods: The open-label, two period cross-over study was conducted in 20 healthy Chinese subjects with different CYP2C19 genotypes receiving clopidogrel, rabeprazole or the two drugs, respectively. All the volunteers were divided into two groups, poor metabolizers (PMs) and extensive metabolizers (EMs), depending on CYP2C19 genotypes. Blood samples were collected at baseline and at 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 h after administration. The plasma concentrations of rabeprazole and clopidogrel were analyzed by LC-MS/MS and ADP-induced platelet aggregation was detected by the optical turbidimetric method., Results: There were no significant differences in the mean plasma concentration-time curves of clopidogrel (CPG), the inactive metabolite clopidogrel carboxylic acid (CPG-CA), the active metabolite clopidogrel-MP-Derivative (MP-AM), and rabeprazole (RBRZ) according to the co-administration of CPG and RBRZ. There were no major changes in the pharmacokinetics of CPG and RBRZ. The maximal ADP-induced platelet aggregation (2 μmol/L) was decreased in EMs compared with PMs., Conclusion: Co-administration of rabeprazol and clopidogrel did not affect the antiplatelet efficacy of clopidogrel. The CYP2C19 genetic polymorphism may impact the efficacy of clopidogrel.

Objective: Ulipristal acetate is a novel selective progesterone receptor modulator for the treatment of benign gynecological conditions such as uterine myoma. As a Biopharmaceutical Classification System (BCS) II compound, it is highly soluble at low pH but has low solubility at neutral conditions. Esomeprazole, a proton pump inhibitor used widely for treatment of gastric and duodenal ulcers, efficiently increases gastric pH. Thus, the aim of this study was to determine the effects of esomeprazole on the pharmacokinetics of ulipristal acetate., Materials and Methods: This was a nonrandomized, single sequence, 2 period, open, study in 18 healthy female subjects. Subjects received oral ulipristal acetate tablets (10 mg) once on Days 1 and 13 and daily esomeprazole administrations (20 mg) from Days 9 through 14., Results: Co-administration of esomeprazole decreased geometric mean Cmax of ulipristal acetate by 65% (geometric mean ratio point estimate (90% CI): 0.35 (0.28 - 0.42)), and delayed median tmax from 0.75 to 1.00 h (Hodges-Lehmann estimate of difference (90% CI): tmax 0.63 (0.25 - 1.25)) but had minor effects on AUCs of +15% and +11% (geometric mean ratio point estimates (90% CI): AUC0-t 1.15 (1.02 - 1.31) and AUC0-∞ (1.11 (0.98 - 1.27)), respectively. A total of 6 adverse events were reported by 4 subjects, none of them being serious., Conclusions: Concomitant use of ulipristal acetate with esomeprazole at therapeutic concentrations led to a modified absorption rate while exposure in terms of AUC remained close to bioequivalence limits. In the context of chronic administration of ulipristal acetate, no clinically significant effects are expected from co-administration with drugs increasing gastric pH.

Omeprazole is metabolized in the liver mainly by the polymorphic CYP2C19 enzyme. Considerable ethnic differences have been reported in the pharmacokinetics of omeprazole. The present study was conducted to evaluate the pharmacokinetic parameters of omeprazole after a single oral administration to a random Iranian population. Thirty healthy male subjects, aged 24-31 years, weighing 60-98 kg completed the study. Plasma concentrations of omeprazole were measured over a 12 h period after administration of a single oral dose of 20 mg omeprazole. The pharmacokinetic parameters were calculated from the plasma concentration-time profiles. Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) was used to quantify 5-hydroxyomeprazole. The mean area under the concentration-time curve (AUC) from time zero to infinity (AUC(∞) ) values of omeprazole and the corresponding coefficient of variation (CV%) was 987.3 ng h/ml (65%). In general, most subjects showed a normal distribution. Only one subject showed a very high AUC compared with the corresponding mean AUC level. This subject had the highest half-life and the lowest rate of elimination. The omeprazole metabolic ratio for this subject was 2.9, while for the others it was in the range 0.12-0.56. These results are consistent with previous literature that showed the existence of interindividual variability in omeprazole pharmacokinetics, even within a single ethnic group. Differences in the pharmacokinetics could be due to differences in the genetic make-up of subjects as found in their omeprazole metabolic ratios., (Copyright © 2012 John Wiley & Sons, Ltd.)

Objectives: Pantoprazole is metabolized by cytochrome P450 2 C19, which shows genetic polymorphism. The effect of CYP2C19 polymorphism on single-dose pharmacokinetics of oral pantoprazole in healthy volunteers was evaluated., Methods: Pantoprazole pharmacokinetics was determined in 32 healthy volunteers after a 40-mg single oral dose of the drug., Results: Carriers of CYP2C19*2/*2 (n = 2) were characterized by higher, starting from 3.5 h post dose, plasma concentrations of pantoprazole in comparison to wild-type (CYP2C19*1/*1, n = 6) volunteers. In subjects with CYP2C19*17/*17 genotype (n = 6) significantly lower plasma concentrations of the drug vs CYP2C19*1/*1 carriers, were observed from 3.0 h after oral pantoprazole administration. Carriers of CYP2C19*1/*17 (n = 6) and CYP2C19*2/*17 (n = 6) displayed concentration-time profiles comparable to wild-type subjects. CYP2C19*2/*2 volunteers showed a decrease in terminal elimination rate constant (λ(z)) by 83.3%, prolongation of terminal half-life (t(½)) by 572%, a rise in area under the concentration-time curve (AUC) and mean residence time (MRT) by 506% and 259% respectively. Heterozygotes, i.e.. CYP2C19*1/*2 vs CYP2C19*1/*1 were characterized by higher AUC (4.38 ± 1.00 mg·h/L vs 3.00 ± 1.02 mg·h/L, p < 0.05) and C(max) (2.13 ± 0.42 mg/L vs 1.61 ± 0.35 mg/L, p < 0.05) respectively. A significant reduction in MRT (3.83 ± 0.82 h vs 2.73 ± 0.23 h, p < 0.05) in carriers of CYP2C19*17/*17 vs CYP2C19*1/*1 genotypes was observed. Population modeling confirmed the influence of *1/*2, *2/*2, and *17/*17 genotypes on the pharmacokinetics of pantoprazole. The lowest population oral clearance was assessed in the carriers of genotype *2/*2 (3.68 L/h) and the highest value in subjects with genotype *17/*17 (31.13 L/h)., Conclusion: These data suggest that CYP2C19 polymorphism is an important determinant of pantoprazole pharmacokinetics.

Background: Several oral proton pump inhibitors (PPIs) are currently approved for use in pediatric patients in North America and Europe. However, when use of oral therapy is not possible or appropriate, intravenous formulations of PPIs may be helpful. Intravenous esomeprazole is approved in the United States for the short-term treatment of gastroesophageal reflux disease (GERD) with erosive esophagitis in adults and in pediatric patients 1 month to 17 years of age (inclusive) as an alternative to oral therapy. Four open-label, randomized, 2-way crossover studies in adults with GERD found no clinically relevant differences in acid suppression between repeated doses of oral and intravenous esomeprazole. However, the pharmacokinetics of intravenous esomeprazole has not been studied extensively in children., Objective: The aim of this study was to evaluate steady-state pharmacokinetics and tolerability of repeated doses of intravenous esomeprazole in children., Methods: In this multicenter, open-label study, hospitalized patients (0-17 years of age) considered for acid suppression therapy received once-daily intravenous esomeprazole sodium for injection at 0.5 mg/kg (0-1 month of age), 1.0 mg/kg (1-11 months of age), 10 mg (1-5 years of age), 10 or 20 mg (6-11 years of age), or 20 or 40 mg (12-17 years of age) for 4 days. Children 6 to 11 years of age (inclusive) were randomized in a 1:1 ratio to receive esomeprazole 10 or 20 mg, and adolescents 12 to 17 years of age (inclusive) were randomized in a 1:1 ratio to receive esomeprazole 20 or 40 mg. Blood samples were drawn pre- and post-dose. Plasma esomeprazole was measured using reversed-phase liquid chromatography and mass spectrometry. Pharmacokinetic variables were derived using mixed-effects modeling. Adverse events (AEs) were assessed., Results: Fifty-nine patients were randomized and 57 received the study drug. A majority of patients were white (44 white, 5 black/African American, 3 Asian, 5 other) and male (35/57). Fifty patients were eligible for pharmacokinetic analysis, including 6 to 8 patients in each age group. Esomeprazole pharmacokinetics was dose proportional and related to weight and age. Clearance increased with increasing weight and age. The mean AUC(τ) ranged from 6.9 μmol · h/L (10 mg, 6-11 years) to 17.6 μmol · h/L (40 mg, 12-17 years). The mean C(ss,max) ranged from 3.7 μmol/L (0.5 mg/kg, 0-1 month) to 10.5 μmol/L (40 mg, 12-17 years). Thirty-one patients experienced 1 or more AEs; 6 patients experienced 1 or more treatment-unrelated serious AEs., Conclusions: Intravenous esomeprazole at doses resulting in targeted AUC(τ) and C(ss,max) similar to therapeutic exposure in adults appeared to be reasonably well tolerated in this small, select pediatric population. ClinicalTrials.gov identifier: NCT00474019., (Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.)

Background: Some studies have reported a decreased absorption of mycophenolic acid (MPA) from mycophenolate mofetil (MMF) in renal transplanted (RTx) patients under proton-pump inhibitors (PPIs). There is still a lack of information regarding (1) whether this effect occurs when MMF is administered with either tacrolimus or cyclosporine A [calcineurin inhibitors (CNIs)], (2) whether the effect has the same amplitude during the first year after RTx, and finally (3) whether this decrease in exposure is clinically relevant., Methods: We retrospectively analyzed the omeprazole effect in 348 12-hour pharmacokinetic samplings [area under the curve (AUC)(0-12h)] performed on days 7, 14, 30, 60, 180, and 360 after RTx in 77 patients who participated in previous trials., Results: For all periods, the groups with and without PPI did not differ in all variables. By mixed-model analysis of variance, PPI reduced the MPA AUC(0-12h) (P < 0.0008) in the patients under both CNIs mainly due to decreased absorption (P = 0.049). In the tacrolimus group, a lower exposure seemed also due to a decreased MPA reabsorption at 10-12 hours. The PPI effect remains throughout the first year but was clinically more important on day 7. By Cox analysis, the use of PPI was associated with a 25% less chance of being adequately exposed to MPA (95% confidence interval 0.58-0.99, P = 0.04). Similarly, the number of patients underexposed to MPA (AUC < 30 ng·h/mL) was higher at most periods in the PPI group but again not statistically significant., Conclusions: These data indicate that PPI decreases the MPA exposure when associated with both CNIs but particularly in the first week after RTx. In this period, the MMF dose should be increased. This effect lasts throughout the first year but does not seem to be clinically relevant after the first week.

Purpose: Lansoprazole, a cytochrome P450 2C19 (CYP2C19) substrate, has been widely used in children to manage acid-related diseases. CYP2C19 exhibits marked genetic polymorphisms, and distribution of these polymorphisms varies among different ethnic groups. There is limited data regarding the use of probe drugs for determining CYP2C19 activity in children. The aim of this study was to evaluate lansoprazole as an in vivo phenotyping probe for assessing CYP2C19 activity in children., Methods: The CYP2C19*2, *3, and *17 variants were determined in 244 children. Three hours after a single oral dose of lansoprazole (n = 94) or omeprazole (n = 19), plasma lansoprazole and 5-hydroxy lansoprazole or omeprazole and 5-hydroxy omeprazole concentrations were analyzed by high-performance liquid chromatography., Results: The CYP2C19*17 was the most frequent variant allele (24.4%). The group of patients with CYP2C19*17*17 genotype had a 70% lower (p < 0.05) mean lansoprazole plasma concentration compared with the CYP2C19*1*1 genotype group, whereas the CYP2C19*2*2 group had 6.9-fold higher (p < 0.01) mean lansoprazole plasma concentration. Lansoprazole metabolic ratios (lansoprazole/5-hydroxy-lansoprazole) were found to be significantly lower in the *17*17 [mean ± standard deviation (SD); 2.8 ± 2.1] group and higher in the *2*2 group (63.5 ± 12.2) compared with that of the *1*1 genotype group (6.1 ± 4.5)., Conclusion: According to our results from a Turkish pediatric population, lansoprazole is a suitable probe drug for phenotyping CYP2C19. The CYP2C19*2 and *17 variants should be taken into consideration in predicting the clinical outcome of therapy with lansoprazole in the pediatric population.