Review article: the clinical pharmacology of proton pump inhibitors

Abstract

Summary Proton pump inhibitors inhibit the gastric H+/K+‐ATPase via covalent binding to cysteine residues of the proton pump. All proton pump inhibitors must undergo acid accumulation in the parietal cell through protonation, followed by activation mediated by a second protonation at the active secretory canaliculus of the parietal cell. The relative ease with which these steps occur with different proton pump inhibitors underlies differences in their rates of activation, which in turn influence the location of covalent binding and the stability of inhibition. Slow activation is associated with binding to a cysteine residue involved in proton transport that is located deep in the membrane. However, this is inaccessible to the endogenous reducing agents responsible for restoring H+/K+‐ATPase activity, favouring a longer duration of gastric acid inhibition. Pantoprazole and tenatoprazole, a novel proton pump inhibitor which has an imidazopyridine ring in place of the benzimidazole moiety found in other proton pump inhibitors, are activated more slowly than other proton pump inhibitors but their inhibition is resistant to reversal. In addition, tenatoprazole has a greatly extended plasma half‐life in comparison with all other proton pump inhibitors. The chemical and pharmacological characteristics of tenatoprazole give it theoretical advantages over benzimidazole‐based proton pump inhibitors that should translate into improved acid control, particularly during the night.

Proton pump inhibitors: from CYP2C19 pharmacogenetics to precision medicine

“…The acid suppression effect of PPIs relies on the plasma concentration of the parent compound, and the AUC of the PPIs is correlated with the degree of acid inhibition [2,3]. It is therefore logical that variations in the metabolic activity of CYP2C19, for which genetic variability is a major contributor, would ultimately affect the therapeutic activity of PPIs.…”

“…It is well documented that the degree of acid suppression is closely related to variation in pharmacokinetic parameters (PK) of PPIs, specifically, the area under the serum (or plasma) concentration vs. time curve (AUC) [2,3]. The underlying mechanism of this variability is multifactorial and includes genetic and nongenetic factors that can alter the disposition of PPIs.…”

Analysis of the Gastric H,K ATPase for Ion Pathways and Inhibitor Binding Sites

“…This represents a small fraction of the residues surrounding the binding site cavity and emphasizes the generally conserved folding of the backbone in this region. The pyridylmethylsulfinylbenzimidazoles (proton pump inhibitors, PPIs), such as omeprazole 1 and pantoprazole, are in use as primary therapy for acidrelated diseases (6). These compounds are prodrugs that are acid-activated on the luminal side of the enzyme and then form disulfide bonds with specific cysteines in the membrane domain of the H,K ATPase.…”

Relative bioavailability and pharmacokinetic comparison of two different enteric formulations of omeprazole

“…Omeprazole (OPZ), a substituted benzimidazole (5-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl]sylfonyl}-1H-benzimidazole), is a proton pump inhibitor (PPI), which decreases acid production in the stomach and is used for treating various acid-related diseases, such as peptic ulcer, gastroesophageal reflux diseases, and Zollinger-Ellison syndrome (Blum, 1996;Kanazawa et al, 2003;Rezk et al, 2006;Sachs et al, 2006;Poo et al, 2008).…”