Duration of the gastric acid antisecretory effect of AZD0865 in dogs

Background/Aim To investigate the duration of antisecretory effect of AZD0865, a potassium-competitive acid blocker (P-CAB), in dogs. Methods Four Heidenhain pouch dogs received single, oral doses of AZD0865 (1 μmol/kg) and a 3.5-h period of histamine stimulation. Acid output was determined 4, 10 or 24h post-dose during stimulation. Secretory responses were also assessed 24h after 5 days' dosing (1 μmol/kg/day). AZD0865 concentration was determined in plasma at each secretory test, and in gastric juice 23–25 h after single dose (reversed-phase liquid chromatography and fluorescence detection). Results Inhibition of acid output (mean±SE), 4, 10 and 24h after single doses, and 24h after 5th dose was 99±1%, 79±2%, 41±5% and 45±3%, respectively. Systemic exposure to AZD0865 was similar after single and repeated doses. Plasma concentrations at 24h were: 4 nmol/L in 1/4 dogs after single dose; <4 nmol/L in 3/4 after single dose and in 4/4 after repeated dose. AZD0865 concentration in gastric juice was 71.9±14.9 nmol/L. Conclusions AZD0865 (1 μmol/kg) provided almost complete blockade of acid secretion 4h after dose, with inhibition lasting >24 h. At 24h, similar levels of inhibition and AZD0865 plasma concentrations occurred after one and several doses. The concentration of AZD0865 in gastric juice was higher than in plasma. This may reflect concentration of AZD0865 in the parietal cell canaliculus. Thus, the duration of effect outlasts the time AZD0865 is detectable in plasma. Clinical Pharmacology & Therapeutics (2005) 77, P15–P15; doi: 10.1016/j.clpt.2004.11.059