Clopidogrel and proton pump inhibitors: a new drug interaction?

Clopidogrel is a thienopyridine platelet antagonist that irreversibly inhibits the binding of adenosine diphosphate to platelet receptors, ultimately leading to inhibition of platelet aggregation. Clopidogel is a prodrug requiring hepatic bioactivation via cytochrome P450 isozymes (CYP2C19, CYP3A4, CYP3A5) to its pharmacologically active form. Inhibition of cytochrome P450 may interfere with metabolic activation of clopidogrel, reducing its antiplatelet activity and potentially increasing the risk of thrombosis. More recently, the cytochrome P450 2C19 pathway has been identified as the key pathway in clopidogrel bioactivation. Medications and, more recently, genetic mutations have been shown to affect the activity of the cytochrome P450 2C19 pathway. Proton pump inhibitors (PPIs), commonly used for prophylaxis and treatment of gastrointestinal bleeding, have been shown to inhibit the cytochrome P450 2C19 pathway to various degrees. Thus, it is biologically plausible that use of a PPI could impair the metabolic activation of clopidogrel through inhibition of this pathway. Recent clinical studies have illustrated the potential metabolic interaction between PPIs and clopidogrel, which could result in inhibition of the antiplatelet activity of clopidogrel. The clinical significance of these studies is reviewed below.