An update on drug-drug interactions associated with proton pump inhibitors
Expert Opinion on Drug Metabolism & Toxicology Journal: Published on: 11 Jul 2022
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.
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.
PPIs cause significant increases in gastric pH, which may alter the absorption of weak acids or bases. They may inhibit the absorption of drugs such as griseofulvin, ketoconazole, itraconazole, iron salts, vitamin B12, cefpodoxime, and enoxacin, many of which are weak bases and require acid for absorption.
PPIs are metabolized to varying degrees by the hepatic cytochrome P450 enzymatic system and may alter drug metabolism by induction or inhibition of the cytochrome P enzymes. This is an important consideration in patients taking medications with a narrow therapeutic window, such as diazepam, phenytoin, and warfarin.
TAKE HOME MESSAGE:
Numerous drug–drug interactions have been reported with PPIs, the most frequent mechanism being the increase in gastric pH, which alters the absorption and bioavailability of numerous treatments with pH-dependent solubility.
This review will discuss the latest updates on drug-drug interactions with PPIs, focusing on the last 10-year publications in the following areas: anti-infective agents, anticancer drugs, antiplatelet agents and anticoagulants, and antidiabetics.
Some formulations have been developed to prevent these gastric pH-dependent drug–drug interactions. Their efficacy should be further demonstrated large-scale comparative prospective studies.
Another frequent mechanism is the competitive inhibition of cytochromes P450, notably CYP2C19 and CYP3A4
Some PPIs, omeprazole, esomeprazole, and lansoprazole, have high CYP2C19 inhibitory potential. The others, pantoprazole, rabeprazole, and dexlansoprazole, have a low CYP2C19 inhibitory potential, and may be preferred according to the co-prescribed treatments.
All described drug–drug interactions do not have significant clinical impact, but clinicians should be careful with the potentially clinically significant ones.
They must also understand that because of the retrospective nature of most of the studies assessing clinical relevance, the level of evidence is quite low.
According to the co-prescribed drugs, dose adjustment or therapeutic drug monitoring may be required.
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Introduction: Proton pump inhibitors (PPIs) block the gastric H/K-ATPase, therefore inhibiting acid gastric secretion, leading to an increased pH (>4). They account for an extremely high number of prescriptions worldwide. Numerous drug-drug interactions have been described with PPIs, but all the described interactions do not have clinical significance.
Areas covered: This review will discuss the latest updates on drug-drug interactions with PPIs, focusing on the last 10-year publications in the following areas: anti-infective agents, anticancer drugs, antiplatelet agents and anticoagulants, and antidiabetics.
Expert opinion: Although pharmacokinetic interactions of PPIs have been described with many drugs, their clinical relevance remains controversial. However, given the extremely high number of people being treated with PPIs, clinicians should remain vigilant for interactions that may be clinically significant and require dose adjustment or therapeutic monitoring. Interestingly, not all PPIs have the same pharmacokinetic and pharmacodynamic profile, with some having a strong potential to inhibit CYP2C19, such as omeprazole, esomeprazole, and lansoprazole, while others, pantoprazole, rabeprazole, and dexlansoprazole, are weak CYP2C19 inhibitors. These may be preferred depending on co-prescribed treatments. In addition, new formulations have been developed to prevent some of the gastric pH-dependent drug interactions and should be evaluated in further large-scale prospective comparative studies.
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