摘要：In the present study, we evaluated the effect of the novel acid pump antagonist 7-(4-fluorobenzyloxy)-2,3-dimethyl-1-{[(1 S ,2 S )-2-methylcyclopropyl]methyl}-1 H -pyrrolo[2,3- d ]pyridazine (CS-526) on the intragastric acidity of cynomolgus monkeys. The study was performed in a crossover manner with five male animals. CS-526 was administered orally or intravenously at doses of 3.0, 10 and 30 mg/kg, or 0.3, 1.0 and 3.0 mg/kg, respectively. The time period in which the intragastric pH was 4.0 or more (TimepH≥4.0) and the median pH were calculated for 24 h after the administration. The intragastric pH was elevated after CS-526 treatment. The TimepH≥4.0 was increased in a dose-dependent manner ( p =0.0292) in the oral administration, and the median pH was also increased in a dose-dependent fashion ( p =0.0491) in the intravenous administration. The plasma concentration of CS-526 and its metabolite R-130185 was increased after oral and intravenous administration of CS-526, except for one animal which did not show any detectable amount of R-130185 after intravenous administration at the lowest dose. The area under the time–concentration curve of the active component was increased in the dose proportional manner after oral and intravenous administration. The absolute bioavailability of the active component was estimated to be approximately 1%. Correlation between the pharmacodynamic parameters and the pharmacokinetic parameters was observed in oral ( p =0.0029—0.0745), but not in intravenous administration ( p =0.0558—0.2789). In conclusion, oral and intravenous administration of CS-526 showed inhibition on gastric acidity in cynomolgus monkeys using intragastric pH-metry and some pharmacokinetic and pharmacodynamic parameters were well correlated.
