Drug-Drug Interaction Profiles of Proton Pump Inhibitors

Proton pump inhibitors (PPIs) are widely prescribed for the treatment of gastric acid-related disorders and the eradication of Helicobacter pylori. In addition, they are routinely prescribed for the prevention of gastrointestinal bleeding in patients receiving a dual antiplatelet therapy consisting of clopidogrel and aspirin (acetylsalicylic acid) after myocardial infarction or percutaneous coronary intervention and stenting. Because PPIs are given to these patients for long periods, there is a concern about the potential for clinically significant drug-drug interactions (DDIs) with concomitantly administered medications. Because PPIs give rise to profound and long-lasting elevation of intragastric pH, it is not surprising that they interfere with the absorption of concurrent medications. Drug solubility may be substantially reduced at neutral pH compared with acidic conditions. In this context, PPIs have been shown to reduce the bioavailability of many clinically relevant drugs (e.g. ketoconazole, atazanavir) by 50% or more compared with the control values. Soon after the introduction of omeprazole (a prototype PPI) into the market, it was reported that omeprazole was associated with 30% and 10% reductions in systemic clearance of diazepam and phenytoin, respectively. In vitro studies demonstrating the inhibitory effects of omeprazole on the metabolism of these drugs with human liver microsomes gave a mechanistic explanation for the DDIs. Numerous subsequent studies have been performed to investigate the DDI potential of PPIs associated with the metabolic inhibition of cytochrome P450 (GYP) enzyme activities; however, most such attempts have failed to find clinically relevant results. Nevertheless, recent large-scale clinical trials have raised concerns about possible DDIs between PPIs and an antiplatelet drug, clopidogrel. It has been suggested that coadministration of PPIs with a dual antiplatelet therapy consisting of clopidogrel and aspirin may attenuate the anti-aggregation effects of those medications and augment the risk of cardiovascular ischaemic events. There is a possibility that PPIs may elicit detrimental effects by inhibiting CYP2C19-dominated metabolism of clopidogrel to its active metabolite. Further studies are urgently required to clarify the mechanism of this DDI and to explore new aspects of the DDI potential of PPIs.