CYP2C19 polymorphism and proton pump inhibitors.
Proton pump inhibitors such as omeprazole (esomeprazole), lansoprazole, pantoprazole and rabeprazole are eliminated by the hepatic route and the polymorphic CYP2C19 is mainly involved in their metabolism. In different populations three phenotypes have been identified: extensive metabolizers, poor metabolizers and individuals carrying one wild type and one mutant allele (het extensive metabolizers). Systemic exposure to the proton pump inhibitors as expressed by the AUC (area under the plasma level time profiles) is 5-12-times higher in poor metabolizers than in extensive metabolizers. As the pharmacodynamic response (elevation of intragastric pH) to the proton pump inhibitors is related directly to their AUC, a much higher pH can be monitored over 24 hr in poor metabolizers than in extensive metabolizers. Furthermore, clinical efficacy of all proton pump inhibitors depend on maintaining intragastric pH above certain threshold levels and significantly higher eradication rates of Helicobacter pylori have been observed in patients of the poor metabolizers and het extensive metabolizers phenotype if compared to extensive metabolizers. Likewise, limited data suggest that proton pump inhibitors-induced healing rates in gastro-oesophageal reflux disease are apparently higher in poor metabolizers/het extensive metabolizers than in extensive metabolizers of CYP2C19. Therefore initial genotyping for this enzyme and higher dosage in extensive metabolizers is likely to improve the clinical efficacy of proton pump inhibitors.
Klotz
Ulrich
U
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstr. 112, D-70376 Stuttgart, Germany. ulrich.klotz@ikp-stuttgart.de
Schwab
Matthias
M
Treiber
Gerhard
G
D000897:Anti-Ulcer Agents / Q000494:pharmacology / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D002986:Clinical Trials as Topic; D065731:Cytochrome P-450 CYP2C19; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005744:Gastric Acid / Q000378:metabolism; D005764:Gastroesophageal Reflux / Q000188:drug therapy; D016480:Helicobacter pylori / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D054328:Proton Pump Inhibitors
D000897:Anti-Ulcer Agents; D004791:Enzyme Inhibitors; D054328:Proton Pump Inhibitors; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19