The proton pump inhibitor, omeprazole, but not lansoprazole or pantoprazole, is a metabolism-dependent inhibitor of CYP2C19: Implications for coadministration with clopidogrel

Brian W. Ogilvie, Phyllis Yerino, Faraz Kazmi, David B. Buckley, Amin Rostami-Hodjegan, Brandy L. Paris, Paul Toren, Andrew Parkinson

    Research output: Contribution to journalArticlepeer-review

    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 directacting 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 μM [lansoprazole; maximum plasma concentration (C max) = 2.2 μM] to 93 μM (pantoprazole; C max = 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 (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 μM 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 Romeprazole, lansoprazole, or pantoprazole, as irreversible (or quasiirreversible) 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. Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics.
    Original languageEnglish
    Pages (from-to)2020-2033
    Number of pages13
    JournalDrug Metabolism and Disposition
    Volume39
    Issue number11
    DOIs
    Publication statusPublished - Nov 2011

    Fingerprint

    Dive into the research topics of 'The proton pump inhibitor, omeprazole, but not lansoprazole or pantoprazole, is a metabolism-dependent inhibitor of CYP2C19: Implications for coadministration with clopidogrel'. Together they form a unique fingerprint.

    Cite this