Clinical impact of CYP2C19 polymorphism on the action of proton pump inhibitors: a review of a special problem.
Proton pump inhibitors (e.g. omeprazole/esomeprazole, lansoprazole, pantoprazole, rabeprazole) have a prominent role in the short- and long-term management of acid-related intestinal disease. They are eliminated by the hepatic route and the polymorphic CYP2C19 is involved in their metabolism. Three phenotypes have been identified in various populations: extensive metabolizers (homEM), poor metabolizers (PM) and individuals carrying one wild type and one mutant allele (hetEM). Therefore, systemic drug exposure (AUC) varies widely between these three populations and the AUC for omeprazole, lansoprazole and rabeprazole are approximately 7.5-, 4.5- and 4-fold higher in PM than in homEM. Since the pharmacodynamic response to proton pump inhibitors (PPIs) is related to their AUC, intragastric pH is much more elevated in PM (median around 6) and hetEM (4 - 5) than in homEM (3 - 4). This genotype-dependent increase in AUC and intragastric pH has clinical consequences because the healing rate in peptic ulcer (PU, target pH > or = 3) and gastroesophageal reflux disease (GERD, target pH > or = 4) and the eradication of Helicobacter pylori (Hp) depend on a long-lasting (> or = 16 hours) and effective inhibition of acid secretion. Several clinical studies have shown that PM and hetEM benefit from an approximately 18% higher Hp eradication rate compared to homEM when standard dosages of PPIs are administered orally. In our own study with lansoprazole (+ amoxicillin, clarithromycin, metronidazole) the eradication rates were 100, 98 and 80% in PM, hetEM and homEM, respectively, and in patients with GERD treated with lansoprazole (30 mg/day) the healing rates after 8 weeks were much higher in PM (85 - 100%) and hetEM (68 - 95%) than in homEM (46 - 77%). In a further study with esomeprazole (40 mg/day) in 205 patients with GERD we were surprised to observe that the healing rate after 4 weeks was not dependent on the CYP2C19 genotype. In an accompanying pharmacokinetic trial in 10 patients with GERD, both esomeprazole and 5-OH-esomeprazole (formed by CYP2C19) plasma levels and those of omeprazole-sulfone (formed by CYP3A4) were determined. Based on the calculated metabolic ratios it could be shown that CYP3A4 plays a major role in kinetics of esomeprozale, particularly after multiple dosing when there is a metabolic shift in favor of the formation of the sulfone. In conclusion, for most PPIs the activity of CYP2C 19 determines the level of drug exposure (AUC), pharmacodynamic response (elevation of intragastric pH and serum levels of gastrin) and clinical outcome (Hp eradication, healing rates of PU and GERD). Thus, a genotype-adjusted dosage regimen will improve therapeutic efficacy of PPIs.
Klotz
U
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Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany. ulrich.klotz@ikp-stuttgart.de
D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000493:pharmacokinetics / Q000494:pharmacology; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000502:physiology; D065731:Cytochrome P-450 CYP2C19; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D064098:Esomeprazole; D006801:Humans; D064747:Lansoprazole; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000502:physiology; D009853:Omeprazole / Q000493:pharmacokinetics / Q000494:pharmacology; D011110:Polymorphism, Genetic; D054328:Proton Pump Inhibitors
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000897:Anti-Ulcer Agents; D004791:Enzyme Inhibitors; D054328:Proton Pump Inhibitors; D064747:Lansoprazole; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D009853:Omeprazole; D064098:Esomeprazole