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)

Cytochrome P450 (CYP) 2C19 mediates the major metabolic transformations of the proton pump inhibitors (PPIs) omeprazole, pantoprazole, lansoprazole, esomeprazole, and rabeprazole. Genetic polymorphism of CYP2C19 can lead to significant phenotypic variation in the activity of this isoenzyme and thus in the metabolism of PPIs. We systematically reviewed the pharmacogenetic studies of PPIs with respect to the effects of CYP2C19 polymorphism on the clinical outcomes of PPI therapy. We searched MEDLINE (January 1966-August 2002) and EMBASE (January 1988-August 2002) for English-language articles on the pharmacogenetics of PPIs; the search was supplemented by a bibliographic review of all relevant articles. Seventeen pertinent citations were identified, and the quality (level) of evidence for each was categorized according to the rating scale of the United States Preventive Services Task Force. We found that the relationship between CYP2C19 genetic polymorphism and clinical outcomes after PPI therapy has not yet been clearly delineated. Virtually all pharmacogenetic studies of PPIs have been performed in Japanese men; thus, the clinical relevance of CYP2C19 genetic polymorphism in non-Asian patients and women is unknown. Differences among dual- and triple-therapy drug regimens make it difficult to compare H. pylori eradication studies and assess their applicability to current practice patterns. Drug adherence, a pivotal factor in the success of eradication therapy, was addressed in only four trials. Future directions for research include performing more studies with larger sample sizes, particularly in non-Asian populations and women; measuring plasma PPI concentrations to directly correlate H. pylori infection and ulcer cure rates with plasma drug availability; expanding the study population to patients with gastroesophageal reflux disease; and exploring the influence of CYP3A4 in the success or failure of PPI therapy. Although CYP2C19 genotyping is currently only a research instrument, it may be a valuable clinical tool in select patients to ensure optimal PPI therapy.
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PMID:Pharmacogenetics of the proton pump inhibitors: a systematic review. 1268 Apr 76

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