43 The sulfonamide then binds covalently to key cysteine groups on the extracellular domain of the proton pump to cause prolonged inhibition of the gastric acid secretion. Acid secretion is generally only restored through the recruitment of pumps that were previously at rest in the cytosol or the synthesis of new pumps (H+K+-exchanging ATPAse), which have a synthetic half life of approximately 50 h.44 The proton pump inhibitors all have similar short plasma half lives of elimination at

approximately 1 h and since they rapidly concentrate in the acidic secretory canaliculus Navitoclax are unlikely to accumulate elsewhere in the body.45–47 All of the PPIs are highly protein bound (> 95%) and rapidly metabolized by the liver with negligible renal clearance.48 Most PPIs are metabolized predominantly through the cytochrome P450 (CYP) enzyme systems, more specifically through CYP2C19. The majority of omeprazole metabolism

occurs through his pathway, while esomeprazole >  pantoprazole > lansoprazole are less metabolized via this pathway. Rabeprazole is the PPI least metabolized via CYP2C19; the majority of its metabolism occurs via a non-enzymatic pathway.28 Genetic polymorphisms of CYP2C19 expression account for the main inter-individual differences in PPI metabolism. However, the evidence for clinically significant sequelae from such interactions MI-503 as a result of inhibition of CYP450 has been conflicting.28,49,50 Study of the pharmaco-dynamics of clopidogrel and PPI demonstrates that they are very rapidly metabolized by the cytochrome P450 system and the authors suggest the chance of interaction would appear to be minimized. This review of the evidence regarding the apparent PPI and clopidogrel interaction is instructive from a number of perspectives. First, it is clear that in patients on clopidogrel and/or aspirin, bleeding results in significantly worse outcomes

Second, co-prescription of a PPI reduces bleeding and is incorporated into the current American Heart Association and American selleck chemical College of Gastroenterology guidelines, which recommend the use of a proton pump inhibitor (PPI) for the prevention of gastrointestinal bleeding in patients on antiplatelet therapy who are at high risk of bleeding.9 Third, examination of the pharmaco-kinetics and -dynamics of clopidogrel and PPIs, suggest that the opportunity for interaction between the two agents is limited, given the rapid concentration of the PPIs (weak bases) in the acidic secretory canaliculus and rapid metabolism of both PPIs and clopidogrel into their respective metabolites. Finally the available clinical evidence for the clopidogrel and PPI interaction is open to serious criticism and certainly not unequivocal.