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 IC50 values varying from 1.2 μM [lansoprazole; maximum plasma concentration (Cmax) = 2.2 μM] to 93 μM (pantoprazole; Cmax = 6.5 μM). In addition, we identified omeprazole, esomeprazole, R-omeprazole, and omeprazole sulfone as MDIs of CYP2C19 (they caused IC50 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 (IC50 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 KI (inhibitor concentration that supports half the maximal rate of inactivation) values of 1.7 to 9.1 μM and kinact (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.
Footnotes
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.111.041293.
↵ The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- PPI
- proton pump inhibitor
- AUC
- area under the plasma concentration versus time curve
- CLint
- in vitro intrinsic clearance
- Cmax
- maximum plasma concentration
- P450
- cytochrome P450
- DDI
- drug-drug interaction
- EM
- extensive metabolizer
- HLM
- human liver microsomes
- Ki
- inhibition constant
- KI
- inhibitor concentration that supports half the maximal rate of inactivation
- kinact
- maximal rate of enzyme inactivation
- LC/MS-MS
- liquid chromatography/tandem mass spectrometry
- MTDI
- University of Washington Metabolism and Transport Drug Interaction database
- MDI
- metabolism-dependent inhibitor
- FDA
- U.S. Food and Drug Administration
- DMSO
- dimethyl sulfoxide
- PM
- poor metabolizer
- MSM
- mechanistic state model
- MDM
- mechanistic dynamic model
- amu
- atomic mass units.
- Received June 22, 2011.
- Accepted July 27, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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