Abstract
Six proton pump inhibitors (PPIs), omeprazole, lansoprazole, esomeprazole, dexlansoprazole, pantoprazole, and rabeprazole, were shown to be weak inhibitors of cytochromes P450 (CYP3A4, -2B6, -2D6, -2C9, -2C8, and -1A2) in human liver microsomes. In most cases, IC50 values were greater than 40 μM, except for dexlansoprazole and lansoprazole with CYP1A2 (IC50 = ∼8 μM) and esomeprazole with CYP2C8 (IC50 = 31 μM). With the exception of CYP2C19 inhibition by omeprazole and esomeprazole (IC50 ratio, 2.5 to 5.9), there was no evidence for a marked time-dependent shift in IC50 (IC50 ratio, ≤2) after a 30-min preincubation with NADPH. In the absence of preincubation, lansoprazole (IC50 = 0.73 μM) and esomeprazole (IC50 = 3.7 μM) were the most potent CYP2C19 inhibitors, followed by dexlansoprazole and omeprazole (IC50 = ∼7.0 μM). Rabeprazole and pantoprazole (IC50 = ≥25 μM) were the weakest. A similar ranking was obtained with recombinant CYP2C19. Despite the IC50 ranking, after consideration of plasma levels (static and dynamic), protein binding, and metabolism-dependent inhibition, it is concluded that omeprazole and esomeprazole are the most potent CYP2C19 inhibitors. This was confirmed after the incubation of the individual PPIs with human primary hepatocytes (in the presence of human serum) and by monitoring their impact on diazepam N-demethylase activity at a low concentration of diazepam (2 μM). Data described herein are consistent with reports that PPIs are mostly weak inhibitors of cytochromes P450 in vivo. However, two members of the PPI class (esomeprazole and omeprazole) are more likely to serve as clinically relevant inhibitors of CYP2C19.
Footnotes
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↵ The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.
ABBREVIATIONS:
- PPI
- proton pump inhibitor
- P450
- cytochrome P450
- HLM
- human liver microsomes
- r
- recombinant
- CEC
- 3-cyano-7-ethoxy-coumarin
- fu,inc
- free fraction in the incubation
- IC50
- concentration of inhibitor that decreases activity by 50% (not corrected for fu,inc)
- IC50(t)
- concentration of inhibitor that decreases activity by 50% after a preincubation time (t)
- IC50(u)
- IC50 corrected for fu,inc
- Cmax
- maximal concentration in plasma
- Cmax,u
- maximal concentration in plasma corrected for free fraction in plasma
- Cmax,portal
- maximal concentration in portal vein
- Cmax,portal,u
- maximal concentration in portal vein corrected for plasma protein binding
- DMSO
- dimethyl sulfoxide
- RF-MS/MS
- RapidFire-mass spectrometry
- KI
- inhibitor concentration that supports half the maximal rate of inactivation
- kinact
- maximal rate of inactivation
- [I]
- concentration of inhibitor
- Ki,u
- Ki corrected for fu,inc
- KI,u
- KI corrected for fu,inc
- kdeg
- rate of P450 (CYP2C19) holoenzyme degradation in the absence of inhibitor
- fa
- fraction absorbed
- ka
- absorption rate constant
- kobs
- rate constant for inactivation at a given concentration of inhibitor
- IV
- intravenous
- AUC
- area under the curve
- fm,2C19
- fraction cleared via CYP2C19
- PM
- poor metabolizer
- EM
- extensive metabolizer
- AUCPM
- AUC in poor metabolizers
- AUCEM
- AUC in extensive metabolizers
- AUCi
- AUC in the presence of inhibitor
- AUCc
- AUC in the absence of inhibitor
- CI
- confidence interval
- FR
- fractional activity remaining.
- Received March 7, 2012.
- Accepted May 30, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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