Drug-Drug Interaction Profiles of Proton Pump Inhibitors

Abstract

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 (CYP) 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.

Proton Pump Inhibitors in cancer patients: How useful they are? A review of the most common indications for their use

“…Drug interference induced by PPIs is not limited at the level of GI absorption. Data showing interaction with liver cytochrome enzymes and metabolism of other drugs are available in literature: PPIs are potent inhibitors of CYP2C19 although the clinical relevance is uncertain (Ogawa and Echizen, 2010).…”

“…Finally, it should be remembered that other drugs, potentially used in cancer patients, are exposed to significant variation in circulating levels, when co-administered with PPIs: Itraconazole, Carbamazepine, Diazepam, Citalopram are examples of proven interactions (Ogawa and Echizen, 2010).…”

Erratum to: Clinical Pharmacokinetics of Sacubitril/Valsartan (LCZ696): A Novel Angiotensin Receptor–Neprilysin Inhibitor

“…Omeprazole, a proton pump inhibitor and a substrate of CYP3A4 and CYP2C19, is widely used for the treatment of gastric acid-related disorders in patients with different diseases including cardiovascular disease [54][55][56]. An increase in gastric pH following administration of omeprazole can interfere with the absorption of co-medications with pH-dependent solubility [55].…”

Effets indésirables des inhibiteurs de la pompe à proton : faut-il craindre de les prescrire au long cours ?

“…La prise d'un IPP pourrait théoriquement amé-liorer la biodisponibilité des médicaments pour lesquels une part importante de la dose ingérée est normalement hydrolysée en milieu acide (ex. pénicillines), mais cette interaction n'a pas été précisément étudiée [56]. Enfin, il a été montré que l'oméprazole augmentait la biodisponibilité de la digoxine [57] et de la nifé-dipine [58] en inhibant au niveau intestinal l'isoenzyme 3A4 du cytochrome P450 (CYP) et la glycoprotéine P, un des principaux transporteurs d'efflux.…”

“…Le cas particulier de l'interaction entre les IPP et le clopidogrel, un antiagrégant dont l'efficacité dépend de sa bioactivation par le CYP 2C19, est étudié avec attention, sans qu'il ne soit possible pour l'heure de confirmer son impact clinique [56,63] …”