R&D Operations Department, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawaku, Tokyo 140-8710, Japan.
Biol Pharm Bull. 2009 Dec;32(12):2010-7. doi: 10.1248/bpb.32.2010.
In the present study, we evaluated the effect of the novel acid pump antagonist 7-(4-fluorobenzyloxy)-2,3-dimethyl-1-{[(1S,2S)-2-methylcyclopropyl]methyl}-1H-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 (Time(pH > or = 4.0)) and the median pH were calculated for 24 h after the administration. The intragastric pH was elevated after CS-526 treatment. The Time(pH > or = 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.
在本研究中，我们评估了新型酸泵拮抗剂 7-(4-氟苄氧基）-2,3-二甲基-1-[(1S,2S)-2-甲基环丙基]甲基]-1H-吡咯并[2,3-d]嘧啶（CS-526）对食蟹猴胃内酸度的影响。该研究采用交叉方式进行，共纳入 5 只雄性动物。CS-526 分别以 3.0、10 和 30mg/kg 或 0.3、1.0 和 3.0mg/kg 的剂量口服或静脉给药。计算给药后 24 小时内胃内 pH 值为 4.0 或更高（Time(pH > or = 4.0)）和中位数 pH 值。CS-526 治疗后胃内 pH 值升高。口服给药时，Time(pH > or = 4.0)呈剂量依赖性增加（p = 0.0292），静脉给药时中位数 pH 值也呈剂量依赖性增加（p = 0.0491）。CS-526 口服和静脉给药后，CS-526 的血浆浓度及其代谢物 R-130185 增加，除了一只动物在最低剂量静脉给药后未检测到任何可检测量的 R-130185。口服和静脉给药后，活性成分的时间浓度曲线下面积呈剂量比例增加。活性成分的绝对生物利用度估计约为 1%。口服（p = 0.0029-0.0745）和静脉（p = 0.0558-0.2789）时均观察到药效学参数与药代动力学参数之间存在相关性。结论：食蟹猴胃内 pH 监测显示，CS-526 口服和静脉给药均能抑制胃酸分泌，部分药代动力学和药效学参数具有良好的相关性。
