Delineating CYP2C19-Mediated Interactions: Network Pharmacology Investigation of Ilaprazole and Clopidogrel versus Conventional Proton Pump Inhibitors.

Background: Clopidogrel, an antiplatelet drug commonly used in cardiovascular disease, is metabolized by the liver mainly through CYP2C19. Concomitant use of Proton pump inhibitors along with clopidogrel may affect the potency of clopidogrel by CYP2C19 inhibition. However, a novel PPI, ilaprazole is known to differ in its pharmacokinetic features, given the potential differences between ilaprazole's interactions and their metabolism with clopidogrel. Network pharmacology investigation could be a useful tool to evaluate the drug-drug interaction between them.

Methodology: The molecular structures and targets were retrieved from PubChem and SwissTargetPrediction to establish the information related to the identified drugs. The possible shared targets between the clopidogrel and PPIs were explored by a Venn analysis. Subsequently, Protein-Protein Interaction networks were established using the STRING database. Hub genes were also determined using the Cytoscape cytoHubba plugin.

Results & discussion: Ilaprazole (13.6%) and pantoprazole (13.6%) were characterized by fewer targets being shared with clopidogrel compared to conventional PPIs (14.9%). Moreover, CYP2C19 was not a hub gene in ilaprazole and pantoprazole interactions, which indicated no significant CYP2C19 involvement. On the other hand, CYP2C19 functioned as a hub gene in the interactions with rabeprazole, lansoprazole, dexlansoprazole, omeprazole, and esomeprazole. As a result, patients receiving pantoprazole and ilaprazole would be at a lower risk for developing adverse cardiovascular events by maintaining the clopidogrel therapeutic effect.

Conclusion: The application of the network pharmacology technique allows us to consider the potential for different effects of PPIs on clopidogrel and its metabolism via CYP2C19. There is a lower chance of experiencing adverse effects from an interaction between ilaprazole and clopidogrel as ilaprazole has not been linked to CYP2C19. More research is necessary to confirm these results and provide clinical guidance for patients undergoing clopidogrel and PPI combination therapy.