INTERACTION OF THE NON‐STEROIDAL ANTIINFLAMMATORY DRUG FLUFENAMIC ACID WITH GASTRIC ACID SECRETION AND H+/K+ ‐ATPase

SUMMARY 1. The effects of the non-steroidal anti-inflammatory drug (NSAID) flufenamic acid on H+production in isolated and enriched guinea-pig parietal cells and on H+/K+-ATPase activity in ion-tight inside-out membrane vesicles from pig gastric mucosa were studied. 2. At low concentrations (0.1 and 1.0 μmol/L), flufenamic acid increased the secretory response of parietal cells to dibutyryl cyclic AMP (dbcAMP). At higher concentrations (10 and 100 μmol/L) it progressively inhibited basal and dbcAMP-stimulated acid production. 3. Flufenamic acid (10 μmol/L) increased K+ (0.5–10.0 mmol/L) and K+ (0.5–1.0 mmol/L) plus gramicidin-stimulated ATPase activity in gastric membrane vesicles. The Km value for K+ (1.6 and 1.0 mmol/L in the absence and presence of gramicidin, respectively) was decreased to 0.8 and 0.5 mmol/L, respectively. At higher concentrations (≥ 50 μmol/L), flufenamic acid inhibited K+ plus gramicidin-stimulated ATPase activity (inhibited concentration at 50% [IC50] = 186 μmol/L) and reduced the proton concentration (IC50= 50 μmol/L). 4. It is concluded that flufenamic acid-induced enhancement of dibutyryl cyclic AMP-stimulated H+ production in the parietal cell reflects the stimulation of H+/K+-ATPase. We suggest that activation of the enzyme involves increased affinity of K+ towards the K+-binding site of the enzyme and/ or increased KC1 permeability at the vesicle membrane. The inhibitory action of the drug on H+production in parietal cells results from a detergent and/or protonophoric-like action at the apical parietal cell membrane, and from inhibition of H+/K+-ATPase activity.