Evaluation of six proton pump inhibitors as inhibitors of various human cytochromes P450: focus on cytochrome P450 2C19.

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Zvyaga T, Chang SY, Chen C, Yang Z, Vuppugalla R, Hurley J, Thorndike D, Wagner A, Chimalakonda A, Rodrigues AD

Evaluation of six proton pump inhibitors as inhibitors of various human cytochromes P450: focus on cytochrome P450 2C19.

Drug Metab Dispos. 2012 Sep;40(9):1698-711. doi: 10.1124/dmd.112.045575. Epub 2012 May 30.

PubMed ID

22648560 [ View in PubMed

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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, IC(5)(0) values were greater than 40 muM, except for dexlansoprazole and lansoprazole with CYP1A2 (IC(5)(0) = approximately 8 muM) and esomeprazole with CYP2C8 (IC(5)(0) = 31 muM). With the exception of CYP2C19 inhibition by omeprazole and esomeprazole (IC(5)(0) ratio, 2.5 to 5.9), there was no evidence for a marked time-dependent shift in IC(5)(0) (IC(5)(0) ratio, /= 25 muM) were the weakest. A similar ranking was obtained with recombinant CYP2C19. Despite the IC(5)(0) 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 muM). 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.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Rabeprazole	Cytochrome P450 1A2	Protein	Humans	Unknown	Inhibitor Inducer	Details
Rabeprazole	Cytochrome P450 2C8	Protein	Humans	Unknown	Inhibitor	Details
Rabeprazole	Cytochrome P450 2D6	Protein	Humans	Unknown	Inhibitor	Details