Rabeprazole: Mechanism of Action
Rabeprazole is a proton pump inhibitor (PPI) that reduces gastric acid production and is used to treat acid reflux, GERD, and peptic ulcers.
PPIs irreversibly inhibit the H⁺/K⁺-ATPase pump in gastric parietal cells, producing profound and sustained acid suppression.
How It Works
Proton pump inhibitors (PPIs) are prodrugs that accumulate in the acidic secretory canaliculi of gastric parietal cells, where they are protonated and converted to reactive sulfenamide intermediates. These intermediates form covalent disulfide bonds with cysteine residues (primarily Cys813 and Cys892) on the H⁺/K⁺-ATPase enzyme (the proton pump), causing irreversible inhibition. New acid secretion requires synthesis of new pump molecules (t½ ~18 hours), which is why PPIs are dosed once daily and take 2–5 days to reach maximal steady-state efficacy. They inhibit both basal and stimulated acid secretion regardless of stimulus.
Receptor / Target Profile
- •H⁺/K⁺-ATPase (gastric proton pump) — covalent irreversible inhibition at Cys813 and Cys892
- •CYP2C19 — primary metabolic pathway; poor metabolisers achieve 3–5× higher plasma levels
- •CYP3A4 — secondary pathway for esomeprazole and lansoprazole
Pharmacokinetics
Onset of Action
First dose: ~1 hour for gastric pH rise; maximal acid suppression at steady state after 4–5 days
Half-Life (t½)
Plasma t½ short (1–2 hours) but pharmacodynamic effect persists 24+ hours due to irreversible pump binding
Enteric-coated formulations protect against premature acid dissolution. Absorbed in small intestine. Short plasma half-life belies prolonged duration of acid suppression. Rabeprazole is least CYP2C19-dependent — least pharmacogenomic variability. Taken 30–60 minutes before meals for optimal efficacy.
Conditions Treated with Rabeprazole
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