TY - JOUR T1 - Evaluation of Six Proton Pump Inhibitors As Inhibitors of Various Human Cytochromes P450: Focus on Cytochrome P450 2C19 JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1698 LP - 1711 DO - 10.1124/dmd.112.045575 VL - 40 IS - 9 AU - Tatyana Zvyaga AU - Shu-Ying Chang AU - Cliff Chen AU - Zheng Yang AU - Ragini Vuppugalla AU - Jeremy Hurley AU - Denise Thorndike AU - Andrew Wagner AU - Anjaneya Chimalakonda AU - A. David Rodrigues Y1 - 2012/09/01 UR - http://dmd.aspetjournals.org/content/40/9/1698.abstract N2 - 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. ER -