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Proton pump inhibitors (PPIs) are a class of compounds that block the acid secretion from
parietal cells in the stomach, thereby providing relief from acid-related disorders.
Although PPIs are active in the stomach, they are primarily metabolized in the liver
by CPY2C19 and CYP3A4. Above we show the PK pathway for omeprazole, a representative
proton pump inhibitor compound. Omeprazole undergoes stereoselective metabolism, with
the S-isomer converted primarily to 5'O-desmethylomeprazole (5'desmethyl OME) via
CYP2C19, which also catalyzes a secondary conversion of S-omeprazole to
5-hydroxyomeprazole (5-OH OME). CYP3A4 converts S-omeprazole to 3-hydroxyomeprazole.
The primary route of metabolism for the R-isomer of omeprazole is the conversion to
5-hydroxyomeprazole by CYP2C19. Although CYP2C19 catalyzes the same two reactions
for both isomers, the preference is dictated by the stereoisomer of omeprazole.
CYP3A4 can catalyze the formation of any of four different metabolites of R-omeprazole:
5-hydroxyomeprazole (5-OH OME), omeprazole sulfone (OME sulfone),
5'-O-desmethylomeprazole (5'-desmethyl OME), and 3-hydroxyomeprazole (3-OH OME).
Although omeprazole is believed to enter liver cells via diffusion, there is some
evidence to suggest that it can be expelled from the liver cells by ABCB1.
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| Ryan Owen |
| August 8, 2007 |
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