Clinical pharmacology of proton pump inhibitors: what the practising physician needs to know

Proton pump inhibitors (PPIs) [omeprazole, lansoprazole, pantoprazole, rabeprazole and esomeprazole] are widely utilised for the treatment of gastro-oesophageal reflux disease, as well as other acid-related disorders. All PPIs suppress gastric acid secretion by blocking the gastric acid pump, H(+)/K(+)-adenosine triphosphatase (ATPase), but the physicochemical properties of these drugs result in variations in the degree of acid suppression, as well as the speed of onset of acid inhibition. Such differences may impact on the clinical performance of PPIs, and this manuscript discusses data that may help clinicians choose between the available PPIs for specific clinical situations and indications. The characteristics of PPIs that have been developed subsequent to omeprazole offer several advantages over this prototype PPI, particularly with respect to the onset of acid suppression and reduced potential for inter-individual pharmacokinetic variation and drug interactions. Newer agents inhibit H(+)/K(+)-ATPase more rapidly than omeprazole and emerging clinical data support potential clinical benefits resulting from this pharmacological property. Although key pharmacokinetic parameters (time to maximum plasma concentration and elimination half-life) do not differ significantly among PPIs, differences in the hepatic metabolism of these drugs can produce inter-patient variability in acid suppression, in the potential for pharmacokinetic drug interactions and, quite possibly, in clinical efficacy. All PPIs undergo significant hepatic metabolism. Because there is no direct toxicity from PPIs, there is minimal risk from the administration of any of them - even to patients with significant renal or hepatic impairment. However, there are significant genetic polymorphisms for one of the cytochrome P450 (CYP) isoenzymes involved in PPI metabolism (CYP2C19), and this polymorphism has been shown to substantially increase plasma levels of omeprazole, lansoprazole and pantoprazole, but not those of rabeprazole. Hepatic metabolism is also a key determinant of the potential for a given drug to be involved in clinically significant pharmacokinetic drug interactions. Omeprazole has the highest risk for such interactions among PPIs, and rabeprazole and pantoprazole appear to have the lowest risk.Thus, whereas all PPIs have been shown to be generally effective and safely used for the treatment of acid-mediated disorders, there are chemical, pharmacodynamic and pharmacokinetic differences among these drugs that may make certain ones more, or less, suitable for treating different patient subgroups. Of course, the absolute magnitude of risk from any PPI in terms of drug-drug interactions is probably low - excepting interactions occurring as class effects related to acid suppression (e.g. increased digoxin absorption or inability to absorb ketoconazole).