Nonlinear kinetics after high-dose omeprazole caused by saturation of genetically variable CYP2C19
| Autor: | I Roots, K L Rost |
|---|---|
| Rok vydání: | 1996 |
| Předmět: |
Adult
Male Adolescent CYP3A medicine.medical_treatment CYP2C19 Pharmacology 2-Pyridinylmethylsulfinylbenzimidazoles Mixed Function Oxygenases Cytochrome P-450 Enzyme System medicine Humans Enzyme kinetics Enzyme Inhibitors Omeprazole Aged Aged 80 and over chemistry.chemical_classification Chemotherapy Hepatology biology Chemistry Genetic Variation Cytochrome P450 Proton Pump Inhibitors Metabolism Middle Aged Anti-Ulcer Agents Cytochrome P-450 CYP2C19 Phenotype Enzyme biology.protein Female Aryl Hydrocarbon Hydroxylases medicine.drug |
| Zdroj: | Hepatology. 23:1491-1497 |
| ISSN: | 1527-3350 0270-9139 |
| Popis: | Nonlinear kinetics of omeprazole and its metabolites were investigated after treatment with repeated high doses. Extensive metabolizers relating to cytochrome P450 2C19 (CYP2C19) activity received for 1 week either omeprazole at 40 mg/d (n = 14) or 60 mg/d omeprazole twice daily (n = 8). Five poor metabolizers (PMs) received 40 mg/d for 1 week. Comparison of omeprazole plasma kinetics between extensive metabolizers (EMs) and PMs after 40-mg treatment revealed a dominant role of CYP2C19 over cytochrome P450 3A CYP3A in omeprazole metabolism. Comparing the omeprazole doses of 40 mg and 60 mg in eight EMs on day 7 of treatment showed that CYP2C19-dependent plasma clearance of omeprazole and omeprazole sulfone was reduced from 19.0 to 8.4 L/h (P < .001) and from 19.8 to 9.2 L/h (P = .012), respectively. Similarly, formation half-life of 5'-hydroxyomeprazole increased from 0.58 to 1.45 hours (P = .025) with the higher dose. CYP3A-dependent metabolic routes remained unaffected. Thus, high-dose treatment with omeprazole uncovers saturation kinetics for CYP2C19 pathways in EMs, and CYP3A becomes the predominant enzyme of omeprazole elimination. Moreover, these individuals may be at risk for side effects due to high omeprazole concentrations if high-dose omeprazole treatment is combined with drugs inhibiting CYP3A activity. |
| Databáze: | OpenAIRE |
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