Proton pump activation in stimulated parietal cells is regulated by gastric acid secretory capacity: a human study

Abstract

Under normal physiological conditions, gastric acid production is controlled by a negative feedback mechanism. Proton pump inhibitors, such as pantoprazole, inhibit gastric acid secretion by irreversibly binding and inactivating luminally active hydrogen potassium ATPase. Recovery of acid production after treatment with a proton pump inhibitor is driven by new pump synthesis, activation of existing cytoplasmic pumps, or reversal of proton pump inhibition. The authors measured the time course of the inhibition and recovery of acid secretion in healthy volunteers following intravenous administration of pantoprazole to determine the rate of proton pump activation under maximally stimulated conditions. Gastric acid production was measured in 27 Helicobacter pylori negative healthy volunteers (mean age = 31 +/- 7 years; 17 men, 10 women) who received single doses of intravenous pantoprazole (20, 40, 80, or 120 mg) in the presence of a continuous intravenous infusion of 1 ug/kg/h of pentagastrin. From the time profile of acid secretion, the authors described the rate of change of acid output using an irreversible pharmacodynamic response model represented by the equation dR/dt = -k x R x Cpanto + Ln2/PPR x (Ro-R) and correlated the parameter values with demographic factors and gastric acid measurements. Mean stimulated acid output secretion was 21.6 +/- 18.4 mEq/h (range: 1.6-90.5) prior to the administration of pantoprazole and remained steady for 25 hours after placebo administration. Intravenous pantoprazole inhibited acid output in a dose-response fashion, with maximal inhibition (99.9%) occurring after an 80 mg dose. Mean proton pump recovery time was 37.1 +/- 21.0 hours (range: 6.7-75), and recovery was independent of the dose of pantoprazole. There was no association noted between proton pump recovery time and gender, age, race, body weight, or pantoprazole dose. However, there was an inverse correlation between acid output during baseline stimulation and recovery of acid secretion. Mean proton pump recovery time in stimulated normal human volunteers was 37.1 +/- 21.0 hours, with a range of 6.7 to 75 hours. The authors hypothesize that there may be a normal homeostatic mechanism that maintains acid secretory capability within a normal range by altering the rate of proton pump activation dependent on the individual's parietal cell mass. Abnormalities of this process may be responsible for the development of acid peptic disease in susceptible individuals.

Figure 1.

Upper panel: Mean (SE) pantoprazole concentration-time profiles of pantoprazole after administration as 15-minute IV infusions of 10, 20, 40, and 80 mg doses in healthy subjects (see Ferron et al). Curves were obtained by simultaneously fitting equations (3) and (4). Dose-linear pharmacokinetics was assumed to estimate the concentrations after administration of a 120 mg dose. Lower panel: Acid output measurements in pentagastrin-stimulated normal individuals after 15-minute infusions of placebo (closed circles) or intravenous pantoprazole at 10, 20, 40, 80, or 120 mg (open circles, triangles, squares, inverted triangles, or diamonds, respectively). These data have previously been published.^, The curves show estimated “best fits” for these data within each dosage group as calculated by our pharmacodynamic model (see Methods section). The 27 subjects in the lower panel who received pantoprazole form the core of the current analysis. The 8 subjects who received placebo are presented for comparison to show that there is no tachyphylaxis to continuous pentagastrin infusion.

Figure 2.

Correlation of proton pump recovery time with various demographic variables. Upper left panel: Correlation with gender. Upper right panel: Correlation with age. Lower left panel: Correlation with race. Lower right panel: Correlation with body weight.

Figure 3.

Correlation of proton pump recovery time with intravenous pantoprazole dose.

Figure 4.

Correlation of proton pump recovery time with pentagastrin-stimulated acid output in 27 Helicobacter pylori negative normal volunteers. There is an inverse relationship with a slope of 0.42 mEq/h and a y-intercept of 4.94 mEq/h.