Improving CYP2C19 phenotyping using stereoselective omeprazole and 5-hydroxy-omeprazole metabolic ratios

Area of Science:

• Pharmacology
• Drug Metabolism
• Enzyme Kinetics

Background:

• Omeprazole (OME) is a widely used probe drug for phenotyping CYP2C19.
• OME is available as a racemic mixture or as the S-enantiomer.
• Enantioselective metabolism of OME involves CYP2C19 and CYP3A4 enzymes.

Purpose of the Study:

• To investigate the pharmacokinetics of omeprazole and its 5-hydroxy metabolite enantiomers.
• To evaluate the utility of both (R)- and (S)-omeprazole enantiomers in assessing CYP2C19 activity.

Main Methods:

• Utilized pharmacokinetic data from two studies in healthy volunteers.
• Administered omeprazole alone and in combination with CYP inhibitors (voriconazole, fluvoxamine) and an inducer (rifampicin).
• Analyzed the metabolism of omeprazole enantiomers and their 5-hydroxy metabolites.

Main Results:

• Both (R)- and (S)-omeprazole enantiomers demonstrated modulation of CYP2C19 activity.
• (S)-omeprazole showed low metabolic ratio values but still indicated CYP2C19 activity.
• Voriconazole and fluvoxamine significantly impacted omeprazole enantiomer pharmacokinetics.

Conclusions:

• Both (R)- and (S)-omeprazole enantiomers can effectively assess CYP2C19 activity.
• Further research is required to establish precise cut-off values for different CYP2C19 phenotype groups.
• The findings contribute to understanding omeprazole's role in drug-drug interaction studies and pharmacogenetic phenotyping.