Proton pump inhibitors (PPIs), such as lansoprazole and omeprazole, are associated with an increased risk of cardiovascular events; however, the underlying mechanisms remain unclear. We investigated the inhibitory effects of lansoprazole and omeprazole on the formation of cardioprotective epoxyeicosatrienoic acids (EETs) and their downstream metabolites, dihydroxyeicosatrienoic acids (DHETs), from arachidonic acid catalyzed by CYP enzymes. In vitro incubation studies were conducted using human liver microsomes (HLMs), recombinant CYP2C19 (rCYP2C19), and recombinant CYP2C9 (rCYP2C9). IC50 values and R values (a clinical drug–drug interaction risk predictor) were estimated. In HLMs, lansoprazole inhibited the formation of 5,6-, 8,9-, and 11,12-EETs. Omeprazole showed limited inhibition in comparison. In experiments using recombinant enzymes, lansoprazole and omeprazole strongly inhibited EET formation via rCYP2C19, but not rCYP2C9. Lansoprazole exhibited more potent inhibition than omeprazole. Notably, R values for lansoprazole in rCYP2C19 exceeded 1.1 for total EET and DHET formation. Molecular docking analysis suggested that both PPIs may bind to CYP2C19 in a similar pose to a known inhibitor. Docking scores also supported the stronger inhibitory potential of lansoprazole compared to omeprazole. In conclusion, lansoprazole and omeprazole suppress EET formation primarily via CYP2C19 inhibition. The predicted high risk (R > 1.1) for lansoprazole observed in the rCYP2C19 assay suggests a potential mechanism for the increased cardiovascular risk. Further clinical studies are warranted to validate these findings.
Kobayashi et al. (Tue,) studied this question.