Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017168 (gastroesophageal reflux disease)
 11,783 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proton pump inhibitors (PPIs), such as omeprazole, lansoprazole, rabeprazole, esomeprazole, and pantoprazole, are metabolized by cytochrome P450 isoenzyme 2C19 (CYP2C19) in the liver. There are genetic differences that affect the activity of this enzyme. The genotypes of CYP2C19 are classified into three groups: homozygous extensive metabolizer (homEM), heterozygous extensive metabolizer (hetEM), and poor metabolizer (PM). The pharmacokinetics and pharmacodynamics of PPIs differ among the different CYP2C19 genotype groups. Plasma PPI and intragastric pH levels during PPI treatment are the lowest in the homEM group and the highest in the PM group. These CYP2C19 genotype-dependent differences in pharmacokinetics and pharmacodynamics of PPIs are reflected in the cure rates for gastroesophageal reflux disease and Helicobacter pylori infection with PPI-based therapies. The CYP2C19 genotyping test is a useful tool for deciding on the optimal treatment regimen using a PPI, including a dual (PPI plus antibiotic) or a triple (PPI plus two antibiotics) therapy.
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PMID:Pharmacogenomics of proton pump inhibitors. 1501 9

Proton pump inhibitors are now considered the mainstay of treatment for acid-related disease. Although all proton pump inhibitors are highly effective, the antisecretory effects of different drugs in this class are not completely consistent across patients. One reason for this is the acid-suppressing effect of Helicobacter pylori infection, which may augment the actions of proton pump inhibitors. A second important reason for interpatient variability of the effects of proton pump inhibitors on acid secretion involves genetically determined differences in the metabolism of these drugs. This article focuses on the impact of genetic polymorphism of cytochrome P450 (CYP)2C19 on the pharmacokinetics and pharmacodynamics of proton pump inhibitors, particularly rabeprazole. Results reviewed indicate that the metabolism and pharmacokinetics of rabeprazole differ significantly from those of other proton pump inhibitors. Most importantly, the clearance of rabeprazole is largely nonenzymatic and less dependent on CYP2C19 than other drugs in its class. This results in greater consistency of pharmacokinetics for rabeprazole across a wide range of patients with acid-related disease, particularly those with different CYP2C19 genotypes. The pharmacodynamic profile for rabeprazole is also characterized by more rapid suppression of gastric acid secretion than with other proton pump inhibitors, which is also independent of CYP2C19 genotype. The favourable pharmacokinetic/pharmacodynamic profile for rabeprazole has been shown to result in high eradication rates for H. pylori in both normal and poor metabolizers. Pharmacodynamic results have also suggested that rabeprazole may be better suited than omeprazole as on-demand therapy for symptomatic gastro-oesophageal reflux disease. Finally, the use of rabeprazole is not complicated by clinically significant drug-drug interactions of the type that have been reported for omeprazole.
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PMID:Review article: relationship between the metabolism and efficacy of proton pump inhibitors--focus on rabeprazole. 1549 14

Management of gastro-oesophageal reflux disease (GERD) is aimed at reducing oesophageal acid exposure to achieve symptom relief. Therapy has traditionally included advice to the patient on diet and lifestyle management. Recent evidence suggests, however, that some specific dietary modifications may be applicable to the Japanese patient. For example, ingestion of Japanese sweet cakes or rice cakes should be avoided by the Japanese patient with GERD as these foods may provoke heartburn. Pharmacological therapy is, however, usually also required for effective symptom relief. While antacids and histamine H(2)-receptor antagonists have a role in treating mild GERD, effective relief of many cases of oesophagitis is usually only achieved by using proton-pump inhibitors such as lansoprazole, omeprazole and rabeprazole. In the Japanese population, variation in the genetic polymorphism of CYP2C19 (a cytochrome P450 isoenzyme) leads to considerable inter-individual unpredictability in the activity of lansoprazole and omeprazole due to inter-individual differences in the extent to which these agents are metabolized. Consequently, rabeprazole, which does not undergo hepatic biotransformation by CYP2C19, offers significant advantages over the other PPIs as a result of its more predictable activity. This, coupled with its more rapid onset of action, leads to a more efficient and less variable acid-suppressing effect.
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PMID:Review article: treatment for gastro-oesophageal reflux disease--lifestyle advice and medication. 1557 67

Pantoprazole is the third proton pump inhibitor (PPI) to be launched for the treatment of acid-peptic diseases. Like other drugs in this class, pantoprazole causes long-lasting inhibition of acid secretion by inactivating the parietal cell H+/K+-ATPase. Compared with H2 antagonists, pantoprazole results in faster pain relief, more rapid ulcer healing, healing of resistant ulcers and far greater efficacy in oesophageal reflux disease. The three PPIs currently available display almost identical efficacy in the treatment of acid-peptic diseases and when included as part of Helicobacter pylori eradication regimes. However, pantoprazole shows improvements in selectivity and pharmacokinetic properties compared with omeprazole and lansoprazole. The bioavailability of pantoprazole is considerably higher than omeprazole, remains constant upon repeated dosing, and is unaffected by food. Significantly, pantoprazole does not influence hepatic cytochrome P450 activity and does not therefore interact with co-administered drugs. This is in contrast to omeprazole, which inhibits P450, and lansoprazole, which appears to weakly induce multiple metabolic pathways. Although pantoprazole is entering an antisecretory market dominated by omeprazole and ranitidine, it has a number of potential advantages. In this respect it is worth recalling that enhanced specificity and the absence of drug interactions were decisive factors in determining market share in the H2 antagonist era. Pantoprazole may therefore achieve significant market penetration, particularly at the expense of lansoprazole and the H2 blockers.
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PMID:Pantoprazole: a new and more specific proton pump inhibitor. 1598 51

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

Dexloxiglumide is a potent and selective cholecystokinin type 1 (CCK1) receptor antagonist currently under development in a variety of diseases affecting the gastrointestinal tract such as gastro-oesophageal reflux disease, irritable bowel syndrome (IBS), functional dyspepsia, constipation and gastric emptying disorders. In female patients with constipation-predominant IBS, clinical efficacy has been demonstrated following administration of dexloxiglumide 200 mg three times daily. Dexloxiglumide is rapidly and extensively absorbed after single oral administration in humans with an absolute bioavailability of 48%. The incomplete bioavailability is due to both incomplete absorption and hepatic first-pass effect. Following multiple-dose administration of 200 mg three times daily, the accumulation is predictable, indicating time-independent pharmacokinetics. In addition, dexloxiglumide pharmacokinetics are dose-independent after both single and repeated oral three-times-daily doses in the dose range 100-400 mg. Dexloxiglumide absorption window extends from the jejunum to the colon and the drug is a substrate and a weak inhibitor of P-glycoprotein and multidrug resistance protein 1. Plasma protein binding of dexloxiglumide is 94-98% and the drug has a moderate to low volume of distribution in humans. Systemic clearance of dexloxiglumide is moderate and cytochrome P450 (CYP) 3A4/5 and CYP2C9 have been implicated in the metabolism of dexloxiglumide to produce O-demethyl dexloxi-glumide. This metabolite is further oxidised to dexloxiglumide carboxylic acid. These two major metabolites (accounting for up to 50% of dexloxiglumide elimination) have been identified. However, in human plasma the unchanged drug represents the major (up to 91%) component of the metabolic profile. The parent drug is believed to be the major contributor to the efficacy of the compound, since its major metabolites are pharmacologically inactive. In addition, the drug is a single isomer chiral drug (eutomer) that does not undergo chiral inversion into its pharmacologically inactive enantiomer (distomer). After oral administration of (14)C-dexloxiglumide, radioactivity is mainly excreted in bile and in faeces (74% of dose) with much lower excretion in urine (20% of dose). Renal excretion of unchanged dexloxiglumide is low (7% of dose in urine and faeces, 1% of dose in urine) and is dose-independent in the dose range 100-400 mg. As the kidney is a minor contributor to the elimination of dexloxiglumide and/or its metabolites in humans, the pharmacokinetics of the drug should not be affected in patients with renal insufficiency. The pharmacokinetics of dexloxiglumide are also not affected by age, sex and administration with a high-fat breakfast. Mild and moderate liver impairment do not affect the pharmacokinetics of dexloxiglumide but severe liver impairment causes increases in systemic exposure to dexloxiglumide and O-demethyl dexloxiglumide. Thus, the drug should be prescribed with caution in patients with severe hepatic impairment even though no dose adjustment is warranted. The results of different drug interaction studies have indicated that no clinically relevant metabolic and concomitant drug-drug interactions are expected during the clinical use of dexloxiglumide.
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PMID:Pharmacokinetic profile of dexloxiglumide. 1711 94

Low-dose omeprazole is superior to full-dose famotidine in maintenance therapy for gastroesophageal reflux disease, whereas "on-demand" famotidine is more effective for relief of episodes of heartburn. To explain this apparent discrepancy, intragastric pH was measured for 24-hr seven times in eight Japanese Helicobacter pylori-negative cytochrome P450 2C19 extensive metabolizers; on Days 1, 8, and 15 of repeated administration of 10 mg of omeprazole once daily and of 20 mg of famotidine twice daily and before medication. During repeated administration of omeprazole, mean intragastric pH and % time that intragastric pH > 4.0 were significantly higher and became greater. With famotidine, although these parameters were significantly higher, the degrees became smaller. Consequently, acid-suppressive effect was in the order; omeprazole < famotidine on Day 1, omeprazole approximately famotidine on Day 8, and omeprazole >famotidine on Day 15. This discrepancy possibly results from the "potentiation" of acid-suppressive effect of omeprazole and the "tolerance" phenomenon in respect to famotidine.
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PMID:Which has superior acid-suppressive effect, 10 mg omeprazole once daily or 20 mg famotidine twice daily? Effects of single or repeated administration in Japanese Helicobacter pylori-negative CYP2C19 extensive metabolizers. 1721 5

Acid-related disorders are common management problems in clinical practice. The key to effective management is successful suppression of gastric acid production. Proton pump inhibitors (PPIs) are the most potent acid suppressants available and are significantly more effective than histamine H(2) receptor antagonists. Although PPIs are highly effective as a class, differences in their pharmacokinetics, such as bioavailability, elimination half-life and metabolism, may translate into differences in clinical outcomes. A new immediate-release omeprazole has been introduced, which allows rapid absorption. This has been shown to produce significantly better nocturnal gastric acid control than delayed-release tablets. The bioavailability of rabeprazole on day 1 is greater than with other PPIs, and this may translate into faster onset of symptom relief for patients with gastro-oesophageal reflux disease. On the other hand, the bioavailability of esomeprazole increases 3-fold at day 5, and it has been shown that on day 5, esomeprazole provided significantly more effective control of gastric acid than other PPIs. The exact clinical significance of these observations remains to be determined. There is genetic polymorphism in PPI metabolism via cytochrome P450 2C19. In Helicobacter pylori eradication, a significantly lower eradication rate was seen in extensive metabolisers with omeprazole and lansoprazole but not with rabeprazole. The oesophagitis healing rate was lower in extensive metabolisers with lansoprazole but not with rabeprazole. The currently available PPIs have short elimination half-lives ranging from 1 to 1.5 hours. Tenatoprazole is a new PPI that has a 5- to 7-fold longer elimination half-life than current PPIs. It could be potentially more useful for the treatment of gastro-esophageal reflux disease and nocturnal acid breakthrough than other PPIs.
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PMID:Proton pump inhibitors: do differences in pharmacokinetics translate into differences in clinical outcomes? 1807 14

Proton pump inhibitors (PPI) are most effective for the gastroesophageal reflux disease (GERD) treatment. The effectiveness of PPI in the long-term treatment of GERD is similar. However, the PPI are different according to fast onset and duration of antisecretory action, pH-selectivity, metabolism, interactions with other medicines and dosage forms. In some clinical situations, these differences can be significant. In this article was described features of the pharmacokinetics of PPI. It was shown that the early stages of treatment of certain advantages in speed of onset of effect is lansoprazole, which potentially increases the patient's adherence to treatment. Metabolism in the cytochrome P450 system provides the lowest profile of pantoprazole drug interactions, making it the most secure in the presence of GERD in a patient comorbidities and need for drugs used to treat it.
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PMID:[How to choose correct proton pump inhibitors to patients with GERD?]. 2049 11

The main therapeutic agent for gastroesophageal reflux disease (GERD) is a proton pump inhibitor (PPI). Plasma levels and the acid inhibitory effect of PPIs depend on the activity of cytochrome P450 (CYP) 2C19, which is polymorphic. Genotypes of CYP2C19 are classified into three groups: rapid metabolizers (RMs: *1/*1), intermediate metabolizers (IMs: *1/*X), and poor metabolizers (PMs: *X/*X), where *1 and X represent the wild type and the mutant allele, respectively. RMs include ultra-rapid metabolizers, who possess the CYP2C19*17 allele. The pharmacokinetics and pharmacodynamics of PPIs differ among different CYP2C19 genotype groups. Plasma PPI levels and intragastric pH values during PPI treatment are lowest in the RM group, intermediate in the IM group, and highest in the PM group. These CYP2C19-genotype-dependent differences in the pharmacokinetics and pharmacodynamics of PPIs influence the healing and recurrence of GERD during PPI treatment, suggesting the need for CYP2C19 genotype-based tailored therapy for GERD. CYP2C19 pharmacogenetics should be taken into consideration for the personalization of PPI-based therapy. However, the clinical usefulness of CYP2C19 genotype testing in GERD therapy should be verified in clinical studies.
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PMID:Individualized therapy for gastroesophageal reflux disease: potential impact of pharmacogenetic testing based on CYP2C19. 2287 40


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