Gastric Acid Pump Research Articles

Modeled Hepatic/Plasma Exposures of Omeprazole Prescribed Alone in Cytochrome P450 2C19 Poor Metabolizers Are Likely Associated with Hepatic Toxicity Reported in a Japanese Adverse Event Database.

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.

Evaluation of the comparative pharmacokinetic properties of a new orally disintegrating tablet of tegoprazan in healthy Korean subjects.

Tegoprazan is a differentiated gastric acid-pump blocker and belongs to a class of potassium-competitive acid secretion blockers. An orally disintegrating tablet (ODT) of tegoprazan was developed to improve patient compliance. The purpose of this study was to compare pharmacokinetics (PK) and safety profiles between the conventional tablet (as the reference drug) and the ODT (as the test drug) of 50 mg tegoprazan in healthy Korean subjects. An open-label, randomized, single-dose, 6-sequence, 3-period crossover study was conducted in 48 healthy subjects. All subjects received a single oral dose of tegoprazan 50mg tablet with water, tegoprazan 50mg ODT with water, and tegoprazan 50mg ODT without water. Serial blood samples were collected up to 48hours after dosing. Plasma concentrations of tegoprazan and its metabolite M1 were measured by LC-MS/MS, and PK parameters were calculated with a non-compartmental method. Safety was evaluated by means of assessed adverse events, physical examinations, laboratory test results as well as measurements of vital signs and ECG throughout the study. A total of 47 subjects completed the study. The 90% confidence intervals of the geometric mean ratios for AUCt, Cmax, and AUCinf of tegoprazan were 0.8873-0.9729, 0.8865-1.0569, and 0.8835-0.9695 for the test drug with water to the reference drug and 0.9169-1.0127, 0.9569-1.1276, and 0.9166-1.0131 for the test drug without water to the reference drug, respectively. There were no serious adverse events, and all adverse events were mild. The PK profiles of tegoprazan were equivalent between the conventional tablet and ODT with or without water. There was no significant difference in the safety profiles. Therefore, the novel ODT of tegoprazan that can be taken without water may improve compliance among patients with acid-related diseases.

Formulation Development and Evaluation of Lansoprazole Mucoadhesive Microsphere

Lansoprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that do not exhibit anticholinergic or histamine H2-receptor antagonist properties, but rather suppress gastric acid secretion by specific inhibition of the (H+,K+)-ATPase enzyme system at the secretary surface of the gastric parietal cell. Because this enzyme system is regarded as the acid (proton) pump within the parietal cell, lansoprazole has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid production. This effect is dose-related and leads to inhibition of both basal and stimulated gastric acid secretion irrespective of the stimulus. The aim of the present study was to develop lansoprazole loaded thiolated chitosan microspheres were prepared by emulsifying method using liquid paraffin light and heavy in ratio of 50:50 as a dispersing medium and glutaraldehyde used as a cross-linking agent. The prepared microspheres were evaluated for mean particle size and particle size distribution, drug content, mucoadhesion measurement and in-vitro drug release. FT-IR spectroscopic analysis was performed to ascertain drug polymer interaction. The release profiles showed first order release behavior up to 12 hours where the highest drug release was 88.89 % of the lansoprazole loaded in the thiolated chitosan microspheres, indicating a strong crosslinking between chitosan and glutaraldehyde. From the results of the present investigation it may be concluded that drug loaded chitosan microspheres can be prepared by a simple technique which avoids the use of complex apparatus and special precautions. Keywords: Lansoprazole, Thiolated chitosan, Microspheres, Glutaraldehyde, Mucoadhesion measurement

Electrochemical Redox Behavior of Omeprazole Using a Glassy Carbon Electrode

AbstractThe electrochemical redox behavior of omeprazole (OMZ), a gastric acid pump inhibitor, was investigated at a glassy carbon electrode using cyclic, differential pulse and square‐wave voltammetry over a wide pH range. The pH‐dependent oxidation occurs in two irreversible consecutive charge transfer reactions. Adsorption of the nonelectroactive product was also observed. The first oxidation involves removal of one electron, followed by deprotonation and leads to the formation of a hydroxylated species. The second oxidation process is related to the hydroxyl and amino groups in the benzimidazole moiety. The reduction is irreversible, also pH‐dependent, and occurs in a single step at the sulfoxide group in a diffusion‐controlled mechanism. The diffusion coefficient of omeprazole was calculated to be DOMZ=2.31×10−6 cm2 s−1.

5-Substituted 1 H-pyrrolo[3,2- b]pyridines as inhibitors of gastric acid secretion

A series of novel 1 H-pyrrolo[3,2- b]pyridines was prepared relying on a copper iodide catalyzed cyclization of 2-prop-1-ynylpyridin-3-amines. A structure–activity relationship was established focusing on the influence of the substitution pattern in position 1, 3, and 5 of the heterocycle on anti-secretory activity, lipophilicity, and p K a value. Some of the compounds proved to be potent inhibitors of the gastric acid pump.

Novel imidazo[1,2- a]pyrazine derivatives as potent reversible inhibitors of the gastric H +/K +-ATPase

A series of novel 6-substituted imidazo[1,2- a]pyrazines were synthesized via palladium catalyzed amino- or alkoxycarbonylation as key step. The anti-secretory activity of these compounds has been assessed in a binding assay against H +/K +-ATPase from hog gastric mucosa. Some of the compounds proved to be potent inhibitors of the gastric acid pump.

Preparation of tetrahydroimidazo[2,1- a]isoquinolines and their use as inhibitors of gastric acid secretion

A series of novel tetrahydroimidazo[2,1- a]isoquinolines was prepared based on a hetero Diels–Alder reaction between an enamine and 1,2,4-triazine as key step. A structure–activity relationship was established focussing on the influence of the substitution pattern in position 3 and 6 of the heterocycle on antisecretory activity, lipophilicity, and p K a value. Potent inhibitors of the gastric acid pump were identified.

Novel indanyl-substituted imidazo[1,2- a]pyridines as potent reversible inhibitors of the gastric H +/K +-ATPase

A series of novel 8-indanylamino- and 8-indanyloxy-substituted imidazo[1,2- a]pyridines with reduced lipophilicity was synthesized from easily accessible starting compounds. The anti-secretory activity of these compounds has been assessed in a competitive binding assay against H +/K +-ATPase from hog gastric mucosa. Some of the compounds proved to be potent inhibitors of the gastric acid pump.

Clinical pharmacological aspects of the proton pump inhibitor therapy – importance of pharmacogenetic differences in the clinical practice

Proton pump inhibitors (PPIs) are widely used for the treatment of gastroesophageal reflux disease, as well as other acid-related disorders. Omeprazole, lansoprazole, pantoprazole, rabeprazole and esomeprazole effectively suppress gastric acid secretion by blocking the gastric acid pump, H+/K+ -adenosine triphosphatase (ATPase). Understanding the pharmacokinetic properties of PPIs and examining the pharmacogenetic differences may help clinicians to optimize PPI therapy and to perform individual treatment, especially in non-responder patients with GERD or ulcer or after failed eradication therapy.

Characterization of the inhibitory activity of tenatoprazole on the gastric H +,K +-ATPase in vitro and in vivo

Tenatoprazole is a prodrug of the proton pump inhibitor (PPI) class, which is converted to the active sulfenamide or sulfenic acid by acid in the secretory canaliculus of the stimulated parietal cell of the stomach. This active species binds to luminally accessible cysteines of the gastric H +,K +-ATPase resulting in disulfide formation and acid secretion inhibition. Tenatoprazole binds at the catalytic subunit of the gastric acid pump with a stoichiometry of 2.6 nmol mg −1 of the enzyme in vitro. In vivo, maximum binding of tenatoprazole was 2.9 nmol mg −1 of the enzyme at 2 h after IV administration. The binding sites of tenatoprazole were in the TM5/6 region at Cys813 and Cys822 as shown by tryptic and thermolysin digestion of the ATPase labeled by tenatoprazole. Decay of tenatoprazole binding on the gastric H +,K +-ATPase consisted of two components. One was relatively fast, with a half-life 3.9 h due to reversal of binding at cysteine 813, and the other was a plateau phase corresponding to ATPase turnover reflecting binding at cysteine 822 that also results in sustained inhibition in the presence of reducing agents in vitro. The stability of inhibition and the long plasma half-life of tenatoprazole should result in prolonged inhibition of acid secretion as compared to omeprazole. Further, the bioavailability of tenatoprazole was two-fold greater in the ( S)-tenatoprazole sodium salt hydrate form as compared to the free form in dogs which is due to differences in the crystal structure and hydrophobic nature of the two forms.

Proton pump inhibitors may reduce tumour resistance

Resistance to cytotoxic agents is a major problem in treating cancer. The mechanisms underlying this phenomenon appear to take advantage of functions involved in the control of cell homeostasis. A mechanism of resistance may be alteration of the tumour microenvironment via changes in the pH gradient between the extracellular environment and the cell cytoplasm. The extracellular pH of solid tumours is significantly more acidic than that of normal tissues, thus impairing the uptake of weakly basic chemotherapeutic drugs and reducing their effect on tumours. An option to revert multi-drug resistance is the use of agents that disrupt the pH gradient in tumours by inhibiting the function of pumps generating the pH gradient, such as vacuolar H+-ATPases (V-H+-ATPases). V-H+-ATPases pump protons across the plasma membrane and across the membranes of various intracellular compartments. Some human tumour cells, particularly those selected for multi-drug resistance, exhibit enhanced V-H+-ATPase activity. A class of V-H+-ATPase inhibitors, called proton pump inhibitors (PPIs), have emerged as the drug class of choice for treating patients with peptic diseases. These drugs inhibit gastric acid secretion by targeting the gastric acid pump, but they also directly inhibit V-H+-ATPases. PPIs (including omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole) are protonable weak bases which selectively accumulate in acidic spaces. Recent findings from our group have shown that PPI pretreatment sensitised tumour cell lines to the effect of cisplatin, 5-fluoro-uracil and vinblastine. PPI pretreatment was associated with the inhibition of V-H+-ATPase activity and an increase of both extracellular pH and the pH of lysosomal organelles, consistent with a cytoplasmic retention of the cytotoxic drugs and targeting to the nucleus in the case of doxorubicin. In vivo experiments showed that oral pretreatment with omeprazole induced a sensitivity of the human solid tumours to anticancer drugs.

Physiology of the Parietal Cell and Therapeutic Implications

The field of acid suppression has been advanced by therapeutics of increasing specificity for inhibiting gastric acid secretion. Particularly important are proton pump inhibitors (PPIs), which inhibit the activity of the gastric acid pump (H+,K(+)-adenosine triphosphatase), the final common step in gastric acid production. Histamine2-receptor antagonists, which act at an early stage of the acid secretion pathway, are less effective and are subject to intolerance. The PPIs are weak bases that undergo accumulation in the acidic space of the secreting parietal cell and are converted in acid to the active thiophilic form, which then forms disulfide bonds with key cysteines of the gastric acid pump. Pantoprazole differs from other PPIs in terms of its reaction with cysteine 822 in the pump and with cysteine 813, a common binding site for all PPIs. Both cysteines are in the sixth transmembrane segment, which is part of the ion transport pathway. This selective binding may have an impact on the dwell time of pantoprazole versus other PPIs because it is inaccessible to reducing agents, in contrast to cysteine 813. Pantoprazole is also very stable (has a slow rate of activation) at neutral pH values compared with other PPIs and has a relatively robust plasma concentration-time curve. These agents are important in the management of duodenal ulcers, nonsteroidal antiinflammatory drug-induced ulcers, gastroesophageal reflux disease, and dyspepsia, but basic pharmacokinetic and pharmacodynamic differences among them may affect clinical utility.

What’s New

What’s New

What's new: proton pump inhibitors and pediatrics.

1. Ashish S. Patel, MD* 2. John F. Pohl, MD* 3. David J. Easley, MD* 1. *Department of Pediatrics, Division of Gastroenterology, Scott and White Hospital, Texas A&M Health Science Center, Temple, TX After completing this article, readers should be able to: 1. Explain why proton pump inhibitors are more effective than histamine2-receptor antagonists. 2. Describe how proton pump inhibitors work. 3. Describe the best delivery system for patients requiring medication through a tube. 4. Identify the proton pump inhibitor currently approved in the United States for intravenous administration. Proton pump inhibitors (PPIs) have become the mainstay of treatment for acid-related gastrointestinal disease in adults since their introduction in 1989. There are several inherent advantages of PPIs compared with the older medication classes of antacids or histamine2-receptor antagonists (H2-RAs). H2-RAs reduce acid secretion only by competing with histamine receptors located in the parietal cell membrane; other cellular receptors that respond to endocrine (gastrin) and neuroendocrine (vagal stimulation) pathways are not affected. As a consequence, H2-RAs do not completely block gastric parietal cell acid production. Unlike H2-RAs, PPIs demonstrate consistent gastric pH control and do not develop tachyphylaxis with repeated dosing. The pharmacology of every PPI involves targeting the gastric acid or proton pump (H+-K+ ATPase), which is situated in parietal cell membranes. After extensive first-pass metabolism in the liver, prodrug accumulates in the canalicular space of the parietal cell and is converted to an active metabolite through an acid-catalyzed reaction. Active drug then irreversibly binds to cysteine residues within the H+-K+ ATPase via a covalent bond. Consequently, PPIs inhibit the final step of gastric acid secretion by blocking proton production. PPIs require an acidic environment within the canalicular space for activation, and proton pumps are maximally exposed on the surfaces of meal-stimulated parietal cells. As a result, administration optimally should occur in a fasting state 30 minutes prior to the first meal of the day. In general, most PPIs …

Clinical pharmacology of proton pump inhibitors: what the practising physician needs to know.

Proton pump inhibitors (PPIs) [omeprazole, lansoprazole, pantoprazole, rabeprazole and esomeprazole] are widely utilised for the treatment of gastro-oesophageal reflux disease, as well as other acid-related disorders. All PPIs suppress gastric acid secretion by blocking the gastric acid pump, H(+)/K(+)-adenosine triphosphatase (ATPase), but the physicochemical properties of these drugs result in variations in the degree of acid suppression, as well as the speed of onset of acid inhibition. Such differences may impact on the clinical performance of PPIs, and this manuscript discusses data that may help clinicians choose between the available PPIs for specific clinical situations and indications. The characteristics of PPIs that have been developed subsequent to omeprazole offer several advantages over this prototype PPI, particularly with respect to the onset of acid suppression and reduced potential for inter-individual pharmacokinetic variation and drug interactions. Newer agents inhibit H(+)/K(+)-ATPase more rapidly than omeprazole and emerging clinical data support potential clinical benefits resulting from this pharmacological property. Although key pharmacokinetic parameters (time to maximum plasma concentration and elimination half-life) do not differ significantly among PPIs, differences in the hepatic metabolism of these drugs can produce inter-patient variability in acid suppression, in the potential for pharmacokinetic drug interactions and, quite possibly, in clinical efficacy. All PPIs undergo significant hepatic metabolism. Because there is no direct toxicity from PPIs, there is minimal risk from the administration of any of them - even to patients with significant renal or hepatic impairment. However, there are significant genetic polymorphisms for one of the cytochrome P450 (CYP) isoenzymes involved in PPI metabolism (CYP2C19), and this polymorphism has been shown to substantially increase plasma levels of omeprazole, lansoprazole and pantoprazole, but not those of rabeprazole. Hepatic metabolism is also a key determinant of the potential for a given drug to be involved in clinically significant pharmacokinetic drug interactions. Omeprazole has the highest risk for such interactions among PPIs, and rabeprazole and pantoprazole appear to have the lowest risk.Thus, whereas all PPIs have been shown to be generally effective and safely used for the treatment of acid-mediated disorders, there are chemical, pharmacodynamic and pharmacokinetic differences among these drugs that may make certain ones more, or less, suitable for treating different patient subgroups. Of course, the absolute magnitude of risk from any PPI in terms of drug-drug interactions is probably low - excepting interactions occurring as class effects related to acid suppression (e.g. increased digoxin absorption or inability to absorb ketoconazole).

Pharmacodynamic modelling of reversible gastric acid pump inhibition in dog and man

H 335/25, a 4-amino quinoline, belongs to a new class of reversible gastric acid pump inhibitors. A potential advantage of such drugs over the irreversible proton pump inhibitors (PPIs) is better control over the effect–time profile. Dose escalation studies were performed to characterize the effect on acid secretion in dogs ( n=24) and healthy male subjects ( n=12). The effect–time profile was delayed compared to the concentration–time profile. A model-based approach, using non-linear mixed effects modelling, was applied to quantify and elucidate the mechanism for the delayed effect. Three different models were investigated: (1) a slow equilibration preceding the formation of drug–enzyme complex, modelled by an effect-compartment, (2) a slow equilibration between free drug, free enzyme and drug–enzyme complex, described by a kinetic binding model, and (3) a delay between enzyme inhibition and the measured response, described by an indirect response model. Model 2 was shown to be superior to models 1 and 3, for both dog and human data. The dissociation rate constant, k off, was estimated to be 0.85 and 0.88 h and the calculated equilibration constant, K d, was 160 and 250 nM in dog and man, respectively. Simulations of the predicted time-course of the effect beyond the 4–5-h observation period was similar for the three models.

Review article: the control of gastric acid and Helicobacter pylori eradication.

This review focuses on the gastric acid pump as a therapeutic target for the control of acid secretion in peptic ulcer and gastro-oesophageal reflux disease. The mechanism of the proton pump inhibitors is discussed as well as their clinical use. The biology of Helicobacter pylori as a gastric denizen is then discussed, with special regard to its mechanisms of acid resistance. Here the properties of the products of the urease gene clusters, ureA, B and ureI, E, F, G and H are explored in order to explain the unique location of this pathogen. The dominant requirement for acid resistance is the presence of a proton gated urea transporter, UreI, which increases access of gastric juice urea to the intrabacterial urease 300-fold. This enables rapid and continuous buffering of the bacterial periplasm to approximately pH 6.0, allowing acid resistance and growth at acidic pH in the presence of 1 mM urea. A hypothesis for the basis of combination therapy for eradication is also presented.

Review article: the pharmacokinetics of rabeprazole in health and disease.

Rabeprazole, a newly developed proton pump inhibitor, has been shown to be effective for the treatment of gastric and duodenal ulcers and for gastro-oesophageal reflux disease. It is a rapid and potent inhibitor of gastric H+,K(+)-ATPase, the gastric acid (proton) pump. The maximum plasma concentration (Cmax) and the area under the plasma concentration time curve (AUC) are linearly related to dose, while the time to maximum plasma concentration (tmax) and elimination half-life (t1/2) are dose-independent. Rabeprazole is extensively metabolized in the liver via the cytochrome P450 enzyme system, and its metabolites are excreted primarily in the urine. Rabeprazole does not accumulate with repeated dosing. Its bioavailability is not influenced by the coingestion of either food or antacids. The pharmacokinetic profile of rabeprazole is substantially altered in the elderly and patients with stable compensated chronic cirrhosis; however, these alterations are not associated with clinically significant abnormalities in laboratory parameters or serious adverse events. The influence of severe decompensated liver disease on the pharmacokinetics of rabeprazole has not been assessed. The pharmacokinetic profile of rabeprazole is not significantly altered by renal dysfunction requiring maintenance haemodialysis. These findings suggest that dosage adjustment is not required in these special patient populations. Caution should be exercised, however, in patients with severe liver disease.

The Na+-K+-ATPase beta1 subunit is associated with the HKalpha2 protein in the rat kidney

The Na+-K+-ATPase beta1 subunit is associated with the HKalpha2 protein in the rat kidney

Sites of Reaction of the Gastric H,K-ATPase with Extracytoplasmic Thiol Reagents

The vesicular gastric H,K-ATPase catalyzes an electroneutral H for K exchange allowing acidification of the intravesicular space. There is a total of 28 cysteines present in the alpha subunit of the gastric H,K-ATPase, of which 10 are found in the predicted transmembrane segments and their connecting loop, and 9 are present in the beta subunit, of which 6 are disulfide-linked. To determine which of these was accessible to extracytoplasmic attack, the enzyme was inhibited by four different substituted 2-pyridylmethylsulfinyl benzimidazoles, 5-methoxy-2-[(4-methoxy-3, 5-dimethyl-2-pyridyl)methylsulfinyl]-1H-benzimidazole (omeprazole), 2-[(4-trifluoroethoxy-3-methyl-2-pyridyl)methylsulfinyl]-1H-ben zimida zole (lansoprazole), 5-difluoromethoxy-2-[3, 4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole (pantoprazole), and 2-[(4-(3-methoxypropoxy)-3-methyl)-2-pyridyl)methylsulfinyl]-1H-++ +benzi midazole (rabeprazole), under acid transporting conditions. All of these compounds are weak bases that accumulate in the acidic space generated by the pump and undergo an acid catalyzed rearrangement to a cationic sulfenamide, which forms disulfides with accessible cysteines. The relative rates of acid activation of these compounds corresponded to the relative rates of inhibition of ATPase activity and acid transport. Fragmentation of the enzyme by trypsin followed by SDS-polyacrylamide gel electrophoresis showed that omeprazole bound covalently to one of the two cysteines in the domains containing the fifth and sixth transmembrane segments and their extracytoplasmic loop and to cysteine 892 in the loop between the seventh and eighth transmembrane segments, but inhibition correlated with the reaction with cysteines in the fifth and sixth domain. Lansoprazole bound to the cysteines in these two domains as well as to cysteine 321 toward the extracytoplasmic end of the third transmembrane segments. Pantoprazole bound only to either cysteine 813 or 822 in the fifth and sixth transmembrane region. The inhibition of Rabeprazole correlated also with its binding to this part of the protein, but this compound continued to bind after full inhibition, eventually binding also to cysteines 321 and 892. No binding was found to any of the cysteines in the seventh to tenth transmembrane segments. Thermolysin digestion of the isolated omeprazole-labeled fifth and sixth transmembrane pair showed that cysteine 813 was the site of labeling. It is concluded that binding of these sided reagents to cysteine 813 in the loop between transmembrane (TM)5 and TM6 is sufficient for inhibition of ATPase activity and acid transport by the gastric acid pump. Of the 10 cysteines present in the membrane and extracytoplasmic domain, only three are exposed sufficiently to allow reactivity with these cationic thiol reagents. The binding to cysteine 813 defines the location of the extracytoplasmic loop between TM5 and TM6 and places the carboxylic acids 820 and 824 conserved between the gastric H,K- and the Na,K-ATPases in TM6, consistent with their assumed role in cation binding.