Сравнение фармакокинетики и метаболизма Pro-Gly-Pro-Leu в крови и мозге крыс при интраназальном и внутривенном введении

Шевченко, К. В.; Вьюнова, Татьяна Владимировна; Andreeva, L. A.; Нагаев, И. Ю.; Shevchenko, Volodymyr Porfyrovych; Мясоедов, Н.Ф.

doi:10.7868/s0869565214170290

Cited by 4 publications

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“…Устойчивость меченых пептидов оценивали после внутривенного введения в яремную вену или интраназального введения крысам Wistar. [23,[42][43][44] При интраназальном введении за 1 ч концентрация Pro-Gly-Pro-Leu в крови падала на 98% (с 67,43 до 1,24 пмоль/мл), что заметно больше, чем при использовании ферментных систем, которые испытывались in vitro. Содержание Pro-Gly-Pro-Leu в крови при внутривенном введении падала более чем на 90% (с 608,24 до 41,63 пмоль/мл).…”

Section: устойчивость пептидов In Vivounclassified

“…При интраназальном способе введения различия в концентрациях пептидов в крови и мозге не столь велики, как при внутривенном способе их введения. Количественная оценка вклада двух возможных путей поступления пептидов в мозг из слизистой носовой полости указывает на соизмеримую роль прямого и опосредованного путей транспорта при интраназальном способе введении [44,49].…”

Section: время минunclassified

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Stability of prolin-containing peptides in biological media

et al. 2019

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New data on peptide drugs have been summarized; their high stability is due to both the introduction of Pro-Gly-Pro in various amino acid sequences and the modification of the glyproline fragment itself. Pro-Gly-Pro-Leu, ACTH(6-9)Pro-Gly-Pro, 5-oxo-Pro-Arg-Pro and 5-oxo-Pro-His-Pro-NH2 were used as proline-containing peptides. Tritiated peptides were obtained: Pro-Gly-Pro-Leu with specific radioactivity of 135 Ci/mmol, ACTH(6-9)Pro-Gly-Pro – 26 Ci/mmol, 5-oxo-Pro-Arg-Pro – 60 Ci/mmol and 5-oxo-Pro-His-Pro-NH2 – 75 Ci/mmol. The concentration of Pro-Gly-Pro-Leu, ACTH(6-9)Pro-Gly-Pro, 5-oxo-Pro-Arg-Pro and 5-oxo-Pro-His-Pro-NH2 in the blood was found to be about 200 times more than in the brain for intranasal administration, and in average 600 times more for intravenous administration. The stability of proline-containing peptides in vitro experiments was determined using different commercially available peptidases (leucine aminopeptidases, dipeptidases, carboxypeptidases B and Y), and using nasal mucus, microsomal fraction of the rat brain (IMPC) and rat blood plasma. During peptidase hydrolysis of Pro-Gly-Pro-Leu, the main metabolites were Gly-Pro-Leu, Pro-Gly-Pro, Gly-Pro and Pro-Gly. For ACTH(6-9)Pro-Gly-Pro, the main metabolites were Phe-Arg-Trp-Pro-Gly-Pro and Trp-Pro-Gly-Pro. In peptidase hydrolysis of 5-oxo-Pro-His-Pro-NH2, the major metabolite was 5-oxo-Pro-His-Pro. It was shown that with different methods of peptides administration the composition of the metabolites formed is different. Based on the data obtained, resistance to enzymatic cleavage of peptides and their metabolic pathways were evaluated. Thus, these new data have shown that the above approaches can be used to prolong the action of glyprolines in living objects. In this case, the degradation of proline-containing peptides occurs mainly not due to the action of proteases, but due to other ways of degradation. In general, the data presented in the review indicate the promise of intranasal way of introducing biologically active peptides into the brain of living organisms.

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Section: устойчивость пептидов In Vivounclassified

Section: время минunclassified

Stability of prolin-containing peptides in biological media

et al. 2019

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“…Кроме того, интересно выяснить, какие метаболиты могут образоваться в результате ферментативного превращения, так как они могут иметь собственную биологическую активность. Например, при разных способах введения Pro-Gly-Pro-Leu содержание образующегося дипептида Gly-Pro может различаться почти в 3 раза [1]. Это нельзя не учитывать в связи с тем, что Gly-Pro обладает выраженным фармакологическим действием, он предотвращает повышение тревожности и снижение уровня ориентировочно-исследовательской активности [2].…”

Section: Introductionunclassified

Study of stability of proline-containing derivatives of dopamine and serotonin in the biological media in vitro experiments

et al. 2019

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Boc-Gly-Pro-DP, Z-Gly-Pro-DP, LA-Gly-Pro-DP, Boc-Gly-Pro-Srt, Z-Gly-Pro-Srt were synthesized for the first time. The stability of these compounds in the presence of leucine aminopeptidase, carboxypeptidase Y, carboxypeptidase B and proline endopeptidase (PEP) was determined. It turned out that the compounds are stable in the presence of aminopeptidases and carboxypeptidases. In the presence of PEP, dopamine (DP) and serotonin (Srt) are cleaved from the synthesized preparations. Thus, new proline-containing Srt and DP derivatives were obtained, Srt and DP could be gradually released from them. This suggest the possibility of a prolonged action of these biologically active compounds on the vital activity of cells and, consequently, of the whole organism.

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