The proton pump inhibitor, omeprazole, but not lansoprazole or pantoprazole, is a metabolism-dependent inhibitor of CYP2C19: implications for coadministration with clopidogrel.
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Ogilvie BW, Yerino P, Kazmi F, Buckley DB, Rostami-Hodjegan A, Paris BL, Toren P, Parkinson A
The proton pump inhibitor, omeprazole, but not lansoprazole or pantoprazole, is a metabolism-dependent inhibitor of CYP2C19: implications for coadministration with clopidogrel.
Drug Metab Dispos. 2011 Nov;39(11):2020-33. doi: 10.1124/dmd.111.041293. Epub 2011 Jul 27.
- PubMed ID
- 21795468 [ View in PubMed]
- Abstract
As a direct-acting inhibitor of CYP2C19 in vitro, lansoprazole is more potent than omeprazole and other proton pump inhibitors (PPIs), but lansoprazole does not cause clinically significant inhibition of CYP2C19 whereas omeprazole does. To investigate this apparent paradox, we evaluated omeprazole, esomeprazole, R-omeprazole, lansoprazole, and pantoprazole for their ability to function as direct-acting and metabolism-dependent inhibitors (MDIs) of CYP2C19 in pooled human liver microsomes (HLM) as well as in cryopreserved hepatocytes and recombinant CYP2C19. In HLM, all PPIs were found to be direct-acting inhibitors of CYP2C19 with IC(50) values varying from 1.2 muM [lansoprazole; maximum plasma concentration (C(max)) = 2.2 muM] to 93 muM (pantoprazole; C(max) = 6.5 muM). In addition, we identified omeprazole, esomeprazole, R-omeprazole, and omeprazole sulfone as MDIs of CYP2C19 (they caused IC(50) shifts after a 30-min preincubation with NADPH-fortified HLM of 4.2-, 10-, 2.5-, and 3.2-fold, respectively), whereas lansoprazole and pantoprazole were not MDIs (IC(50) shifts < 1.5-fold). The metabolism-dependent inhibition of CYP2C19 by omeprazole and esomeprazole was not reversed by ultracentrifugation, suggesting that the inhibition was irreversible (or quasi-irreversible), whereas ultracentrifugation largely reversed such effects of R-omeprazole. Under various conditions, omeprazole inactivated CYP2C19 with K(I) (inhibitor concentration that supports half the maximal rate of inactivation) values of 1.7 to 9.1 muM and k(inact) (maximal rate of enzyme inactivation) values of 0.041 to 0.046 min(-1). This study identified omeprazole, and esomeprazole, but not R-omeprazole, lansoprazole, or pantoprazole, as irreversible (or quasi-irreversible) MDIs of CYP2C19. These results have important implications for the mechanism of the clinical interaction reported between omeprazole and clopidogrel, as well as other CYP2C19 substrates.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Pantoprazole Cytochrome P450 2C19 Protein Humans UnknownSubstrateInhibitorDetails - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareSaquinavirOmeprazole The serum concentration of Saquinavir can be increased when it is combined with Omeprazole. SaquinavirLansoprazole The serum concentration of Saquinavir can be increased when it is combined with Lansoprazole. SaquinavirEsomeprazole The serum concentration of Saquinavir can be increased when it is combined with Esomeprazole. SaquinavirRabeprazole The serum concentration of Saquinavir can be increased when it is combined with Rabeprazole. SaquinavirDexrabeprazole The serum concentration of Saquinavir can be increased when it is combined with Dexrabeprazole.