The Proton Pump Inhibitor, Omeprazole, but Not Lansoprazole or Pantoprazole, Is a Metabolism-Dependent Inhibitor of CYP2C19: Implications for Coadministration with Clopidogrel

Abstract

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 (

Evaluation of Six Proton Pump Inhibitors As Inhibitors of Various Human Cytochromes P450: Focus on Cytochrome P450 2C19

“…The time-dependent shift in IC 50 with (S)-mephenytoin described above is consistent with the observations of Ogilvie et al (2011) and Boulenc et al (2012). In fact, both groups have reported omeprazole (up to 100 M) as a mechanism-based inhibitor of CYP2C19 in HLM and reported K I values ranging from 1.7 to 9.1 M and k inact values ranging from 0.016 to 0.046 min Ϫ1 .…”

“…During the course of the study, it was evident that some of the PPIs behaved as relatively potent inhibitors of CYP2C19 (versus other P450s) and two of them (omeprazole and esomeprazole) also behaved as time-dependent inhibitors. The latter result supports the findings of Ogilvie et al (2011) and Boulenc et al (2012), and the more recent findings of Ohbuchi et al (2012) using 2-oxo-clopidogrel as substrate. Additional studies were conducted with recombinant CYP2C19 (rCYP2C19) using three different substrates , (S)-mephenytoin, and diazepam] and with serum-coincubated human primary hepatocytes using diazepam as substrate.…”

“…Moreover, data for P450s such as CYP2C8, CYP1A2, and CYP2B6 are limited, and there are no reports of various PPIs as time-dependent (metabolism-dependent) inhibitors of P450s (VandenBranden et al, 1996;Ko et al, 1997;Li et al, 2004;Liu et al, 2005;Walsky et al, 2005Walsky et al, , 2006. In fact, there are only two reports describing time-dependent inhibition, with a focus on CYP2C19 (multiple PPIs) or multiple P450s (omeprazole only) (Ogilvie et al, 2011;Boulenc et al, 2012).…”

Identification and weighting of the most critical “real-life” drug–drug interactions with acenocoumarol in a tertiary care hospital

“…To the best of our knowledge, no specific data on the interaction between PPIs and acenocoumarol are available. In a recent in vitro study, esomeprazole and omeprazole were considered as irreversible CYP2C19 inhibitors [37]. Moreover, in a crossover clinical study, a significant DDI was observed between high doses of omeprazole and clopidogrel in healthy subjects [38].…”

Upper Gastrointestinal Symptoms and Cardiovascular Disease

“…Based on in vitro and in vivo data, omeprazole and esomeprazole are the most potent CYP2C19 inhibitors [69]. In vivo, omeprazole and esomeprazole induced 4 and 10 fold functional inhibition of CYP2C19 versus less than 1.5 fold inhibition with lansoprazole and pantoprazole [70]. Rabeprazole has in vitro data showing less inhibition of CYP2C19 than omeprazole and lansoprazole but no in vivo data is available [69].…”