1. Historical Perspective on the Pros and Cons of Coadministration of Proton Pump Inhibitors with Thienopyridine Antiplatelet Drugs (clopidogrel and Prasugrel)

Proton pump inhibitors (PPI) are frequently prescribed with thienopyridine antiplatelet drugs (clopidogrel and prasugrel) for the prevention of upper gastrointestinal mucosal damages. However, recent studies have casted doubt on this combination, because several retrospective cohort studies have suggested a possible detrimental drug interaction between these drugs, particularly in patients undergoing percutaneous coronary intervention and stenting. Lines of robust in vitro and in vivo evidence have shown that PPIs are potent inhibitors of CYP2C19 activity in human liver microsomes and that PPIs reduce the production of the active metabolite of clopidogrel, thus attenuating its antiplatelet activity in patients. In addition, it is known that genetic polymorphism of CYP2C19 is associated with loss of CYP2C19 enzyme activity and that drug interactions of PPI with CYP2C19 substrate drugs occur only in subjects with the extensive metabolizer phenotype of CYP2C19. Because Asians possess higher allelic frequencies of loss-of-function alleles of this CYP isoform than Caucasians, they may be less susceptible to the drug interactions between PPI and thienopyridines. In contrast to clopidogrel, metabolic activation of prasugrel is not affected by PPIs, because multiple CYP isoforms are involved. At present, no prospective randomized studies have been reported, which provide reliable risk-benefit data for the coadministration of PPI with thienopyridine antiplatelet drugs both in Caucasians and Asians.