A Novel Perspective and Approach to Intestinal Octreotide Absorption: Sinomenine-Mediated Reversible Tight Junction Opening and Its Molecular Mechanism

Li, Yuling; Duan, Zhijun; Tian, Yan; Liu, Zhen; Wang, Qiuming

doi:10.3390/ijms140612873

Cited by 14 publications

(12 citation statements)

References 35 publications

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“…In addition, an approximately four-fold increase in absorption was observed when mixed inhibitors were administered to PH rats. Previous studies have indicated that OCT was a substrate for P-gp, MRP2 and CYP3A4 (4,(16)(17)(18). Increased expression or activities of these were observed under a PH state to decrease the intestinal absorption of OCT. To investigate the mechanism underlying the effect of the mixed inhibitors on the first pass effects, we also evaluated the expression levels of P-gp/MRP2/CYP3A4 using RT-PCR, western blot and immunohistochemistry analyses.…”

Section: Discussionmentioning

confidence: 97%

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Inhibition of P-glycoprotein, multidrug resistance-associated protein 2 and cytochrome P450 3A4 improves the oral absorption of octreotide in rats with portal hypertension

Sun

Duan

Liu

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. The aim of the present study was to increase the intestinal transport of octreotide (OCT) by targeting the first-pass impact to identify a potential method for decreasing portal vein pressure (PVP) using oral OCT. Thus, the bioavailability of intestinally absorbed OCT was evaluated in normal rats and rats with portal hypertension (PH) that had been administered P-glycoprotein/multidrug resistance-associated protein 2/cytochrome P450 3A4 (P-gp/MRP2/CYP3A4) inhibitors. The mRNA and protein expression levels of P-gp, MRP2 and CYP3A4 were evaluated in normal and PH rats with or without OCT and the inhibitors using RT-PCR, western blot and immunohistochemical analyses. The potential effects of the inhibitor administration on PVP were also examined. The results suggest that P-gp, MRP2 and CYP3A4 play important roles in prohibiting the enteral absorption of OCT, particularly under a PH environment. Moreover, inhibitors of P-gp, MRP2 and CYP3A4 decrease the first-pass effects of OCT and effectively reduce PVP under PH conditions. Therefore, the present results suggest P-gp, MRP2 and CYP3A4 are key factors in the intestinal absorption of OCT. The inhibition of P-gp, MRP2 and CYP3A4 can markedly decrease the first-pass effects of OCT, and their use may facilitate the use of orally administered OCT.

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Section: Discussionmentioning

confidence: 97%

“…Early and consistent intervention of PH has been recommended in the clinic to reduce morbidity and mortality of patients with cirrhosis; however, currently, there are no ideal oral medicines for limiting PH due to side effects and poor efficacy (4).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of P-glycoprotein, multidrug resistance-associated protein 2 and cytochrome P450 3A4 improves the oral absorption of octreotide in rats with portal hypertension

Sun

Duan

Liu

et al. 2016

Experimental and Therapeutic Medicine

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“…For OCT, the high molecular weight (C 49 H 66 N 10 O 10 S 2 , MW 1019.3) makes it resulting in low bioavailability after oral administration. Over the past few decades, OCT has attracted a great deal of attenincreasing its lipophilicity [14] , as well as transiently opening tight cell junctions by sinomenine [15] or alkylsaccharides [16] to increase paracellular absorption [14][15][16][17] . Although these attempts have improved the oral absorption of OCT to some extent, they have not yet robustly improved its bioavailability in vivo.…”

Section: Introductionmentioning

confidence: 99%

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

Rao

et al. 2017

Acta Pharmacol Sin

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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.

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“…To lower the effects of FBS on cell growth and protection against LPS treatment as well as support cell survival, for LPS treatment, cells were incubated in DMEM containing 0.5% FBS and 0.1 μg/mL LPS (Sigma-Aldrich, St. Louis, MO, USA) for 24 h as described previously [21]. In OCT-treated groups, cells were pre-treated with 10 μM OCT (Selleckchem, Munich, Germany) for 24 h prior to LPS treatments [22]. For stimulation with Bafiomycin A1 (Baf-A1), cells were incubated in DMEM containing 0.5% FBS and 10 nM Baf-A1 (Sigma-Aldrich) for 24 h. For inhibition of TAK1, (5Z)-7-oxozeaenol (0.5 μM, Sigma-Aldrich) was added into culture and the cells were pre-incubated for 6 h.…”

Section: Cell Culture and Treatmentmentioning

confidence: 99%

“…Cells (passages [22][23][24][25][26][27][28] were maintained in high glucose Dulbecco's modified eagle's medium (DMEM; Gibco, Bethesda, MD, USA) supplemented with 20% fetal bovine serum (FBS; Gibco) under standard conditions (37°C, humidified atmosphere with 5% CO 2 and 95% air). To lower the effects of FBS on cell growth and protection against LPS treatment as well as support cell survival, for LPS treatment, cells were incubated in DMEM containing 0.5% FBS and 0.1 μg/mL LPS (Sigma-Aldrich, St. Louis, MO, USA) for 24 h as described previously [21].…”

Section: Cell Culture and Treatmentmentioning

confidence: 99%

Octreotide Alleviates Autophagy by Up-Regulation of MicroRNA-101 in Intestinal Epithelial Cell Line Caco-2

Li¹,

Wang²,

Gao³

et al. 2018

Cell Physiol Biochem

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Background: Intestinal mucositis is a common side-effect after anti-cancer therapy, which may greatly restrict the therapeutic effects. We aimed to explore the functional role of octreotide (OCT) in lipopolysaccharide (LPS)-induced autophagy of human intestinal epithelial cells as well as the underlying mechanisms. Methods: Cell viability and expression of proteins related to autophagy, AMPK and the mTOR pathway in LPS-treated Caco-2 cells were determined by CCK-8 assay and Western blot analysis, respectively. Effects of OCT on LPS-induced alterations as well as miR-101 expression were measured. Then, miR-101 was aberrantly expressed, and whether OCT alleviated LPS-induced autophagy through miR-101 was tested. Next, whether TGF-β-activated kinase 1 (TAK1) was involved in the regulation of miR-101 in LPS-induced autophagy was studied. Effects of OCT on monolayer permeability and tight junction level were analyzed via measuring transepithelial electrical resistance (TEER) and expression of tight junction proteins. Results: LPS reduced cell viability and increased autophagy through activating AMPK and inhibiting the mTOR pathway in Caco-2 cells. OCT alleviated LPS-induced alterations and repressed degradation of autophagosome. Then, we found that OCT affected autophagy through up-regulating miR-101 in LPS-treated cells. Moreover, miR-101-induced inactivation of AMPK and activation of the mTOR pathway in LPS-treated cells were reversed by inhibition of TAK1 phosphorylation. Finally, we found miR-101 was up-regulated in differentiated cells, and OCT protected the monolayer permeability and tight junction level. Conclusion: OCT repressed autophagy through miR-101-mediated inactivation of TAK1, along with inactivation of AMPK and activation of the mTOR pathway in LPS-treated Caco-2 cells.

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A Novel Perspective and Approach to Intestinal Octreotide Absorption: Sinomenine-Mediated Reversible Tight Junction Opening and Its Molecular Mechanism

Cited by 14 publications

References 35 publications

Inhibition of P-glycoprotein, multidrug resistance-associated protein 2 and cytochrome P450 3A4 improves the oral absorption of octreotide in rats with portal hypertension

Inhibition of P-glycoprotein, multidrug resistance-associated protein 2 and cytochrome P450 3A4 improves the oral absorption of octreotide in rats with portal hypertension

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

Octreotide Alleviates Autophagy by Up-Regulation of MicroRNA-101 in Intestinal Epithelial Cell Line Caco-2

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