Pharmacokinetics and pharmacodynamics of the proton pump inhibitors.

Proton pump inhibitor (PPI) is a prodrug which is activated by acid. Activated PPI binds covalently to the gastric H(+), K(+)-ATPase via disulfide bond. Cys813 is the primary site responsible for the inhibition of acid pump enzyme, where PPIs bind.

Gastric H+,K+-ATPase.

The gastric H(+),K(+)-ATPase is responsible for gastric acid secretion. This ATPase is composed of two subunits, the catalytic α subunit and the structural β subunit. The α subunit with molecular mass of about 100 kDa has 10 transmembrane domains and is strongly associated with the β subunit with a single transmembrane segment and a peptide mass of 35 kDa.

Characterization of a novel potassium-competitive acid blocker of the gastric H,K-ATPase, 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438).

Inhibition of the gastric H,K-ATPase by the potassium-competitive acid blocker (P-CAB) 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine (TAK-438), is strictly K(+)-competitive with a K(i) of 10 nM at pH 7. In contrast to previous P-CABs, this structure has a point positive charge (pK(a) 9.06) allowing for greater accumulation in parietal cells compared with previous P-CABs [e.

Novel approaches to inhibition of gastric acid secretion.

The gastric H,K-adenosine triphosphatase (ATPase) is the primary target for treatment of acid-related diseases. Proton pump inhibitors (PPIs) are weak bases composed of two moieties, a substituted pyridine with a primary pK(a) of about 4.0 that allows selective accumulation in the secretory canaliculus of the parietal cell, and a benzimidazole with a second pK(a) of about 1.

1-Arylsulfonyl-2-(pyridylmethylsulfinyl) benzimidazoles as new proton pump inhibitor prodrugs.

New arylsulfonyl proton pump inhibitor (PPI) prodrug forms were synthesized. These prodrugs provided longer residence time of an effective PPI plasma concentration, resulting in better gastric acid inhibition.

Long lasting inhibitors of the gastric H,K-ATPase.

Proton pump inhibitors (PPIs) are acid-activated prodrugs which covalently bind to the gastric H,K-ATPase on its luminal surface. Only active pumps can be inhibited. The short plasma residence time of current PPIs prevents inhibition of pumps synthesized or activated after the PPI has disappeared, limiting the degree of acid inhibition even with BID administration.

Optimal dose of intravenous pantoprazole in patients with peptic ulcer bleeding requiring endoscopic hemostasis in Korea.

Background And Aim: The lowest effective dose of proton pump inhibitors (PPI) for prevention of peptic ulcer rebleeding remains unclear. The objective of the present study was to evaluate whether low-dose PPI has a similar efficacy to high-dose i.v.

Pharmacology of proton pump inhibitors.

The gastric H,K-ATPase is the primary target for the treatment of acid-related diseases. Proton pump inhibitors (PPIs) are weak bases composed of two moieties, a substituted pyridine with a primary pK(a) of about 4.0, which allows selective accumulation in the secretory canaliculus of the parietal cell, and a benzimidazole with a second pK(a) of about 1.

Simple diagnostic tests to detect toxic alcohol intoxications.

Methanol, ethylene glycol, and diethylene glycol intoxications can produce visual disturbances, neurologic disturbances, acute renal failure, pulmonary dysfunction, cardiac dysfunction, metabolic acidosis, and death. Metabolic acidosis and an increased serum osmolality are important clues to their diagnosis. The former reflects the organic acids produced by metabolism of the parent alcohol, whereas the latter is caused by accumulation of the offending alcohol.

The gastric HK-ATPase: structure, function, and inhibition.

The gastric H,K-ATPase, a member of the P(2)-type ATPase family, is the integral membrane protein responsible for gastric acid secretion. It is an alpha,beta-heterodimeric enzyme that exchanges cytoplasmic hydronium with extracellular potassium. The catalytic alpha subunit has ten transmembrane segments with a cluster of intramembranal carboxylic amino acids located in the middle of the transmembrane segments TM4, TM5,TM6, and TM8.

The gastric H,K ATPase as a drug target: past, present, and future.

The recent progress in therapy if acid disease has relied heavily on the performance of drugs targeted against the H,K ATPase of the stomach and the H2 receptor antagonists. It has become apparent in the last decade that the proton pump is the target that has the likelihood of being the most sustainable area of therapeutic application in the regulation of acid suppression. The process of activation of acid secretion requires a change in location of the ATPase from cytoplasmic tubules into the microvilli of the secretory canaliculus of the parietal cell.

Identification of genomic targets downstream of p38 mitogen-activated protein kinase pathway mediating tumor necrosis factor-alpha signaling.

Inhibition of p38 MAPK suppresses the expression of proinflammatory cytokines such as TNF-alpha and IL-1 beta in macrophages and fibroblast-like synoviocytes (FLS). However, there have been no genomewide studies on the gene targets of p38 MAPK signaling in synoviocytes. Microarray technology was applied to generate a comprehensive analysis of all genes regulated by the p38 MAPK signaling pathway in FLS.

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.

Functional consequences of the oligomeric form of the membrane-bound gastric H,K-ATPase.

Cross-linking and two-dimensional crystallization studies have suggested that the membrane-bound gastric H,K-ATPase might be a dimeric alpha,beta-heterodimer. Effects of an oligomeric structure on the characteristics of E(1), E(2), and phosphoenzyme conformations were examined by measuring binding stoichiometries of acid-stable phosphorylation (EP) from [gamma-(32)P]ATP or (32)P(i) or of binding of [gamma-(32)P]ATP and of a K(+)-competitive imidazonaphthyridine (INT) inhibitor to an enzyme preparation containing approximately 5 nmol of ATPase/mg of protein. At <10 microM MgATP, E(1)[ATP].

Topography of the membrane domain of the liver Na+-dependent bile acid transporter.

The ileal apical and liver basolateral bile acid transporters catalyze the Na+-dependent uptake of these amphipathic molecules in the intestine and liver. They contain nine predicted helical hydrophobic sequences (H1-H9) between the exoplasmic N-glycosylated N terminus and the cytoplasmic C terminus. Previous in vitro translation and in vivo alanine insertion scanning studies gave evidence for either nine or seven transmembrane segments, with H3 and H8 noninserted in the latter model.

Differences in binding properties of two proton pump inhibitors on the gastric H+,K+-ATPase in vivo.

Restoration of acid secretion after treatment with covalently-bound proton pump inhibitors may depend on protein turnover and on reversal of inhibition by reducing agents such as glutathione. Glutathione incubation of the H(+),K(+)-ATPase isolated from omeprazole or pantoprazole-treated rats reversed 88% of the omeprazole inhibition but none of the pantoprazole inhibition. The present study was designed to measure binding properties of omeprazole or pantoprazole in vivo.

Chemistry of covalent inhibition of the gastric (H+, K+)-ATPase by proton pump inhibitors.

Proton pump inhibitors (PPIs), drugs that are widely used for treatment of acid related diseases, are either substituted pyridylmethylsulfinyl benzimidazole or imidazopyridine derivatives. They are all prodrugs that inhibit the acid-secreting gastric (H(+), K(+))-ATPase by acid activation to reactive thiophiles that form disulfide bonds with one or more cysteines accessible from the exoplasmic surface of the enzyme. This unique acid-catalysis mechanism had been ascribed to the nucleophilicity of the pyridine ring.

The basis of differentiation of PPIs.

Proton pump inhibitors (PPIs) were initially believed to block acid secretion permanently. Evidence that acid secretion returned after administration of the compounds led to investigations of the mechanism of this phenomenon. Data showing that, after omeprazole administration, acid secretion returned in less time than the half-life of the pump suggested that more than only new pump synthesis may play a role in acid recovery.

Current trends in the treatment of upper gastrointestinal disease.

The past 25 years have seen an amazing improvement in the treatment and understanding of acid-related disorders. In particular, the introduction of selective histamine receptor antagonists and proton pump inhibitors has made the medical control of acid secretion an effective means of therapy. The demonstration that infection with Helicobacter pylori is responsible for most cases of peptic ulcer disease resulted in another major improvement in therapy in these areas as a result of the eradication of the organism.

Restoration of acid secretion following treatment with proton pump inhibitors.

Background & Aims: Proton pump inhibitors (PPIs) are covalent inhibitors of the gastric H+,K+-adenosine triphosphatase (ATPase) forming disulfide bonds. Recovery of acid secretion after PPI inhibition may be due to de novo synthesis of pump protein and/or disulfide reduction and reactivation of inhibited pump. The half-time of recovery of acid secretion in rats following omeprazole treatment is approximately 15 hours, whereas pump protein half-life is 54 hours.

Proteins released by Helicobacter pylori in vitro.

Secretion of proteins by Helicobacter pylori may contribute to gastric inflammation and epithelial damage. An in vitro analysis was designed to identify proteins released by mechanisms other than nonspecific lysis. The radioactivity of proteins in the supernatant was compared with that of the intact organism by two-dimensional gel phosphorimaging following a 4-h pulse-chase.