Among the somatostatin analogues, octreotide (OCT) is the most commonly used in clinic via intravenous or subcutaneous injection to treat various diseases caused by increased secretion of growth hormone, gastrin or insulin. In order to assesse the feasibility of developing oral formulations of OCT, we conducted systematical pharmacokinetic and pharmacodynamic analyses of OCT in several animal models. The pharmacokinetic studies in rats showed that intragastric administration of OCT had extremely low bioavailability (<0.5%), but it could specifically distribute to the gastric mucosa due to the high expression of somatostatin receptor 2 (SSTR2) in the rat stomach. The pharmacodynamic studies revealed that intragastric administration of OCT dose-dependently protected against gastric mucosal injury (GMI) in mice with WIRS-induced mouse gastric ulcers, which were comparable to those achieved by intravenous injection of OCT, and this effect was markedly attenuated by co-administration of CYN-154806, an antagonist of SSTR2. In pyloric ligation-induced ulcer mice, we further demonstrated that OCT significantly reduced the secretion of gastric acid via down-regulating the level of gastrin, which was responsible for the protective effect of OCT against GMI. Overall, we have provided pharmacokinetic and pharmacodynamic evidence for the feasibility of developing an oral formulation of OCT. Most importantly, the influence of SSTR2 on the pharmacokinetics and pharmacodynamics of OCT suggested that an oral formulation of OCT might be applicable for other clinical indications, including neuroendocrine neoplasms and pituitary adenoma due to the overexpression of SSTR2 on these tumor cells.

中文翻译：

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药代动力学和药效学证据表明，奥曲肽口服制剂可预防胃粘膜损伤。

在生长抑素类似物中，奥曲肽（OCT）是临床上最常用的通过静脉内或皮下注射来治疗由生长激素，胃泌素或胰岛素分泌增加引起的各种疾病。为了评估开发OCT口服制剂的可行性，我们在几种动物模型中进行了OCT的系统药代动力学和药效学分析。在大鼠体内进行的药代动力学研究表明，胃内施用OCT具有极低的生物利用度（<0.5％），但是由于大鼠胃中生长抑素受体2（SSTR2）的高表达，它可以特异性地分布于胃粘膜。药效学研究表明，胃内给药OCT可以剂量依赖性地保护WIRS诱发的小鼠胃溃疡的小鼠免遭胃粘膜损伤（GMI），这与通过静脉内注射OCT所获得的效果相当，并且这种作用被co显着减弱。 -SSTR2拮抗剂CYN-154806的给药。在幽门结扎诱导的溃疡小鼠中，我们进一步证明OCT通过下调胃泌素水平显着减少胃酸的分泌，这是OCT对GMI的保护作用。总体而言，我们为开发OCT口服制剂的可行性提供了药代动力学和药效学证据。最重要的是，