Pharmacokinetic and pharmacodynamic evidence for developing an oral formulation of octreotide against gastric mucosal injury

Authors: Xi-nuo LI1, Tai RAO1, Yang-fan XU1, Kang-rui HU1, Zhang-pei ZHU1, Hao-feng LI1, Dian KANG1, Yu-hao SHAO1, Bo-yu SHEN1, Xiao-xi YIN1, Lin XIE1, Guang-ji WANG1, Yan LIANG1
1 Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
Corresponding to: Guang-ji WANG:, Yan LIANG:,
DOI: 10.1038/aps.2017.159
Received: 12 August 2017
Accepted: 18 October 2017
Advance online: 30 November 2017


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.
Keywords: somatostatin; somatostatin receptors 2; octreotide; CYN-154806; oral formulation; pharmacokinetics; pharmacodynamics; gastric mucosal injury; gastrin; gastric acid