The relationship between the pharmacokinetics of pantoprazole, an irreversible proton pump inhibitor, and its effect on gastric acid secretion was evaluated in humans and rats. Pantoprazole pharmacokinetics were studied in 6 rats (5 mg/kg, i.v.) and 22 healthy volunteers (10 to 80 mg, i.v. and oral). Gastric acid secretion under maximum pentagastrin stimulation was measured after i.v. administration of placebo or pantoprazole in 31 rats (0.12 to 1.15 mg/kg) for 4 hours and in 31 subjects (20 to 120 mg) for 24 hours. Pantoprazole has short half-lives of 0.5 hours in rats and 0.8 hours in humans. After administration of the highest dose, acid secretion was fully inhibited within 1 hour and for the whole observation period in both species. An irreversible pharmacodynamic response model was successfully developed and validated. The apparent reaction rate constants of pantoprazole with the proton pumps were 0.691 L/mg/h in rats and 0.751 L/mg/h in humans, and the apparent recovery rates of the pumps were 0.053 h-1 and 0.031 h-1, respectively. The maximum inhibition and the overall effect of pantoprazole are related to exposure, and the onset is related to initial pantoprazole concentrations. It was concluded that this irreversible response model accurately describes the effect of i.v. and oral pantoprazole on gastric secretion and may be used to predict effects under other dosage regimens.