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

Abstract

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.

Effect of Moxibustion on Intestinal Microbiome in Acute Gastric Ulcer Rats

“…Gastrin (GAS) is mainly mediated by the gas receptor to stimulate the growth of gastric mucosal cells and maintains the integrity of the mucosa [24]. However, EGF mainly increases gastric mucosal blood flow and inhibits apoptosis of gastric mucosal cells, thus maintaining gastrointestinal mucosal integrity [26,27]. In this research, both substances were reversed to normal levels after intervention by moxibustion, which means moxibustion achieved therapeutic effects by regulating brain-gut peptides.…”

Metabolites profiling and pharmacokinetics of troxipide and its pharmacodynamics in rats with gastric ulcer

“…The K a (0.039 ± 0.006, 0.045 ± 0.005, 0.054 ± 0.006 1/min) of the GUGIG were significantly increased ( P < 0.01) compared with the NCGIG (0.014 ± 0.002, 0.019 ± 0.002, 0.022 ± 0.003 1/min). More importantly, from the Concentration–time (C–t) curve the troxipide concentration in the GUGIG was slightly increased compared with that in the NCGIG, suggesting that troxipide was more easily absorbed into the blood of rats with GU than that of NC rats 41 . The T max of the GUGIG was not significantly different from that of the NCGIG, which suggested that the T max not related to dose and disease; this result is consistent with the findings of Gao’s report 23 .…”

Protective role of fruits of Rosa odorata var. gigantea against WIRS-induced gastric mucosal injury in rats by modulating pathway related to inflammation, oxidative stress and apoptosis

“…Gastric mucosal injury is a multifactorial gastrointestinal disease, of which psychological stress is more and more recognized by the public ( Li et al, 2018 ). In our previous study, due to the functional and anatomical similarity to the human stomach, the rats were chosen as the model and administered ethanol intragastrically to simulate human gastric mucosal injury caused by excessive drinking.…”