Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20020 (adenosine triphosphatase)
 3,299 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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).
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PMID:Clinical pharmacology of proton pump inhibitors: what the practising physician needs to know. 1466 53

The development and introduction into clinical practice of proton pump inhibitors (PPIs) have influenced the management of acid-peptic disorders dramatically. PPIs inhibit the gastric hydrogen/potassium adenosine triphosphatase selectively and irreversibly which is the final step in acid secretion. PPIs are currently the most effective form of therapy in acid-peptic diseases. All PPIs are potent, effective and generally safe, but little different in equivalent doses. PPIs undergo hepatic metabolism by cytochrome P450 (CYP) system. Polymorphism of CYP2C19 influences the pharmacokinetics and pharmacodynamics of PPIs. Doses and dosing schemes of PPIs based on CYP2C19 genotype status is expected to increase the efficacy in clinical outcome. The major indication of PPIs are acid-related diseases such as peptic ulcers and their complications, gastroesophageal reflux diseases, Zollinger-Ellison syndrome and eradication of Helicobacter pylori with antibiotics and dyspepsia. The potency and cost-effectiveness of PPIs have extended their clinical uses. However, their widespread and long-term use may limit the therapeutic benefit between efficacy and clinical problems such as acid rebound hypersecretion, enhanced oxyntic gastritis, problems with carcinoids in rodents and long-term concern for gastric cancer development. Further studies are needed to minimize the side effects and to maximize the therapeutic effects of PPIs.
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PMID:[Clinical use of proton pump inhibitors in gastrointestinal diseases]. 1655 71

Proton pump inhibitors (PPIs) have become some of the most frequently prescribed medications for treatment of adults and children. Their effectiveness for treatment of peptic conditions in the pediatric population, including gastric ulcers, gastroesophageal reflux disease (GERD), and Helicobacter pylori infections has been established for children older than 1 year. Studies of the preverbal population of neonates and infants have identified doses that inhibit acid production, but the effectiveness of PPIs in the treatment of GERD has not been established except for the recent approval of esomeprazole treatment of erosive esophagitis in infants. Reasons that have been proposed for this are complex, ranging from GERD not occurring in this population to a lack of histologic identification of esophagitis related to GERD to questions about the validity of symptom scoring systems to identify esophagitis when it occurs in infants. The effectiveness of PPIs relates to their structures, which must undergo acidic activation within the parietal cell to allow the PPI to be ionized and form covalent disulfide bonds with cysteines of the H(+)-K(+)-adenosine triphosphatase (H(+)-K(+)-ATPase). Once the PPI binds to the proton pump, the pump is inactivated. Some PPIs, such as omeprazole and rabeprazole bind to cysteines that are exposed, and their binding can be reversed. After irreversible chemical inhibition of the proton pump, such as occurs with pantoprazole, the recovery of the protein of the pump has a half-life of around 50 h. Cytochrome P450 (CYP) 2C19 and to a lesser degree CYP3A4 clear the PPIs metabolically. These enzymes are immature at birth and reach adult levels of activity by 5-6 months after birth. This parallels studies of the maturation of CYP2C19 to adult levels by roughly the same age after birth. Specific single nucleotide polymorphisms of CYP2C19 reduce clearance proportionally and increase exposure and prolong proton pump inhibition. Prolonged treatment of pediatric patients with PPIs has not caused cancer or significant abnormalities.
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PMID:Proton pump inhibitors in pediatrics : mechanism of action, pharmacokinetics, pharmacogenetics, and pharmacodynamics. 2351 28