Resistance of 1-deamino-(8-D-arginine)-vasopressin to in vitro degradation as compared with arginine vasopressin.

Matsui, Kuniaki; Kimura, Tokihisa; Ota, Kozo; Iitake, Kazuhiro; Miyake, Shoji; Inoue, Minoru; Yoshinaga, Kaoru

doi:10.1507/endocrj1954.32.547

Cited by 12 publications

(6 citation statements)

References 15 publications

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“…Additionally, the peptides oxytocin, vasopressin, and desmopressin feature disulfide bridges between their Cys amino acids, which partially cyclizes their structure and results in high resistance to pepsin cleavage and their subsequent stability in gastric fluids. These results are in line with previous studies showing the high stability of Arg-vasopressin and desmopressin in gastric fluid. , Interestingly, ciclosporin, octreotide, leuprolide, and deslorelin, which all contain pepsin-vulnerable peptide bonds were found to be stable in SGF with pepsin. However, the pepsin-vulnerable amino acids at position 6 in leuprolide and deslorelin, and position 4 in octreotide, are in the d -confirmation, which may render them more resistant to pepsin cleavage due to the enzyme’s specificity toward l -amino acids .…”

Section: Discussionsupporting

confidence: 92%

“…These results are in line with previous studies showing the high stability of Arg-vasopressin and desmopressin in gastric fluid. 11,12 Interestingly, ciclosporin, octreotide, leuprolide and deslorelin which all contain pepsin-vulnerable peptide bonds were found to be stable in SGF with pepsin. However, the pepsin vulnerable amino acids at position 6 in leuprolide and deslorelin, and position 4 in octreotide, are in the D-confirmation which may render them more resistant to pepsin cleavage due to the enzyme's specificity towards L-amino acids.…”

Section: Discussionmentioning

confidence: 99%

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Toward Oral Delivery of Biopharmaceuticals: An Assessment of the Gastrointestinal Stability of 17 Peptide Drugs

et al. 2015

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A major barrier to successful oral delivery of peptide and protein molecules is their inherent instability in the lumen of the gastrointestinal tract. The aim of this study was to determine the stability of 17 disparate peptide drugs (insulin, calcitonin, glucagon, secretin, somatostatin, desmopressin, oxytocin, [Arg(8)]-vasopressin, octreotide, ciclosporin, leuprolide, nafarelin, buserelin, histrelin, [d-Ser](4)-gonadorelin, deslorelin, and goserelin) in gastric and small intestinal fluids from both humans and pigs, and in simulated gastric and intestinal fluids. In human gastric fluid, the larger peptides including somatostatin, calcitonin, secretin, glucagon, and insulin were metabolized rapidly, while the smaller peptides showed good stability. In human small intestinal fluid, however, both small and large peptides degraded rapidly with the exception of the cyclic peptide ciclosporin and the disulfide-bridge containing peptides octreotide and desmopressin, which showed good stability. The stability of peptides in both simulated gastric fluid and pig gastric fluid correlated well with stability in human gastric fluid. However, it was not possible to establish such a correlation with the small intestinal fluids because of the rapid rate of peptide degradation. This work has identified the molecular features in the structure of a wide range of peptides that influence their stability in the environment of the gastrointestinal tract, which in turn will allow for better selection of peptide candidates for oral delivery.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Toward Oral Delivery of Biopharmaceuticals: An Assessment of the Gastrointestinal Stability of 17 Peptide Drugs

et al. 2015

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“…It is inspired by many natural small cyclic proteins, such as cyclosporine and desmopressin 138 . Desmopressin which is a cyclic analogue of vasopressin displays greater resistance to enzymatic degradation than vasopressin 139 . Ring closure of a peptide can be attained by four different ways: head-to-tail (C-terminus to N - terminus), head-to-side chain, side chain-to-tail or side chain-to-side chain, depending on its functional groups 140 .…”

Section: Current Strategies Towards Enhancement Of the Oral Absorption Of Ppsmentioning

confidence: 99%

Oral delivery of proteins and peptides: Challenges, status quo and future perspectives

Zhu

Chen

Paul

et al. 2021

Acta Pharmaceutica Sinica B

163

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Proteins and peptides (PPs) have gradually become more attractive therapeutic molecules than small molecular drugs due to their high selectivity and efficacy, but fewer side effects. Owing to the poor stability and limited permeability through gastrointestinal (GI) tract and epithelia, the therapeutic PPs are usually administered by parenteral route. Given the big demand for oral administration in clinical use, a variety of researches focused on developing new technologies to overcome GI barriers of PPs, such as enteric coating, enzyme inhibitors, permeation enhancers, nanoparticles, as well as intestinal microdevices. Some new technologies have been developed under clinical trials and even on the market. This review summarizes the history, the physiological barriers and the overcoming approaches, current clinical and preclinical technologies, and future prospects of oral delivery of PPs.

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“…Desmopressin is relatively stable in the presence of trypsin and pepsin due to the removal of terminal amino group substitution of L-arginine by D-arginine (Matsui et al, 1985;Wang et al, 2002). However, it is readily degraded by a-chymotrypsin (Kahns et al, 1993;Fredholt et al, 1999;Christophersen et al, 2014).…”

Section: Enzymatic Stability Studiesmentioning

confidence: 99%

Development andin vitroevaluation of an oral SEDDS for desmopressin

et al. 2016

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Context: Self-emulsifying drug delivery systems (SEDDS) are among most promising tools for improving oral peptide bioavailability. Objective: In this study, in vitro protective effect of SEDDS containing desmopressin against presystemic inactivation by glutathione and a-chymotrypsin was evaluated. Materials and methods: The partitioning coefficient (log P) of desmopressin was increased via hydrophobic ion pairing using anionic surfactants. Solubility studies were performed to select the appropriate solvents for SEDDS preparation. Subsequently, droplet size and emulsification properties of 22 SEDDS formulations were evaluated. Moreover, the peptide-surfactant complex was dissolved in two chosen SEDDS formulations. Finally, SEDDS containing desmopressin were characterized regarding lipase stability, toxicity, and in vitro protective effect toward glutathione and a-chymotrypsin. Results: Desmopressin log P was increased from initial À6.13 to 0.33 using sodium docusate. The resulting desmopressin docusate complex (DES/AOT) was incorporated in two different SEDDS formulations, containing Capmul 907 P as main solvent. DES/AOT-SEDDS-F4 (containing 0.07% w/w DES/AOT) was composed of 50% Capmul 907P, 40% Cremophor RH40, and 10% Transcutol. The comparatively more hydrophilic formulation DES/AOT-SEDDS-F15 (containing 0.25% w/w DES/AOT) consisted of 20% Capmul 907P, 40% Acconon MC8-2, and 40% Tween 20. Both formulations were stable toward digestion by lipase and protected desmopressin toward a-chymotrypsin degradation. Moreover, DES/AOT-SEDDS-F4 also protected the peptide from thiol/disulfide exchange reactions with glutathione and was not cytotoxic at a concentration of 0.375% (w/w). Conclusion: DES/AOT-SEDDS-F4 protected desmopressin from in vitro glutathione and a-chymotrypsin degradation. DES/AOT-SEDDS-F4 was metabolically stable and nontoxic. Therefore, it could be considered as a potential delivery system for oral desmopressin administration.

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Resistance of 1-deamino-(8-D-arginine)-vasopressin to in vitro degradation as compared with arginine vasopressin.

Abstract: In order to elucidate the mechanism(s) responsible for the prolonged anti-

Cited by 12 publications

References 15 publications

Toward Oral Delivery of Biopharmaceuticals: An Assessment of the Gastrointestinal Stability of 17 Peptide Drugs

Toward Oral Delivery of Biopharmaceuticals: An Assessment of the Gastrointestinal Stability of 17 Peptide Drugs

Oral delivery of proteins and peptides: Challenges, status quo and future perspectives

Development andin vitroevaluation of an oral SEDDS for desmopressin

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