Chemistry
Omeprazole is a racemate. It contains a tricoordinated sulfinyl sulfur in a pyramidal structure and therefore can exist in equal amounts of both the (S)- and (R)-enantiomers. In the acidic conditions of the canaliculi of parietal cells, both are converted to achiral products (sulfenic acid and sulfenamide configurations) which reacts with a cysteine group in H+/K+ ATPase, thereby inhibiting the ability of the parietal cells to produce gastric acid.
Facing the loss of patent protection and competition from generic drug manufacturers, AstraZeneca developed and heavily marketed esomeprazole (Nexium) as a replacement in 2001. Esomeprazole is the eutomer in the pure form, not a racemate like omeprazole.
Omeprazole undergoes a chiral shift in vivo which converts the inactive (R)-enantiomer to the active (S)-enantiomer doubling the concentration of the active form. This chiral shift is accomplished by the CYP2C19 isozyme of cytochrome P450, which is not found equally in all human populations. Those who do not metabolize the drug effectively are called "poor metabolizers." The proportion of the poor metabolizer phenotype varies widely between populations, from 2–2.5% in African-Americans and white Americans to >20% in Asians; several pharmacogenomics studies have suggested that PPI treatment should be tailored according to CYP2C19 metabolism status.
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