Pharmacokinetic, metabolic, and antidiarrheal properties of (d and l) heptapeptides of sorbin in rodent |
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Authors: | Philippe Nicol Raymond Vienet Gerard Jourdan Cathy Dumas Fatima Abou El Fadil Henri Benech Jean-Marc Grognet Thierry Tarrade Danielle Pansu Monique Descroix-Vagne |
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Institution: | aINSERM Unité 45, Hôpital Edouard Herriot, 69437 Lyon, France;bEcole Pratique des Hautes Etudes, Hôpital Edouard Herriot, 69437 Lyon, France;cCEA, Service de Pharmacologie et d'Immunologie, DRIPP, CE-SACLAY, 91191 Gif-sur-Yvette Cedex, France;dDepartment de Recherche Clinique, Institut Henri Beaufour, 92350 Le Plessis Robinson, France |
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Abstract: | The C-terminal heptapeptide-amide (C7-sorbin) is the minimal biologically active fragment of sorbin inducing an increase in intestinal hydroelectrolytic absorption. An analogue (D7-sorbin), characterized by the replacement of the ultimate C-terminal amino acid l-alanine-amide by d-alanine-amide, was synthetized. For pharmacokinetic studies, D7-sorbin and C7-sorbin were tritium labeled. After IV injection, clearances were 10.6 and 30.2 ml−1 for D7-sorbin and C7-sorbin, respectively, and MRT were 34 and 18 min. After SC administration, Cmax attained 0.41% and 0.12% of the dose/ml, respectively. The IP route showed a 45-min delay before Cmax and a 100% bioavailability for both peptides. D7-sorbin was principally excreted in urine, as shown by balance study, and in part in intact form, as controlled by mass spectrometry. D7-sorbin induced a significant decrease of the VIP-induced ileal secretion, previously observed with C7-sorbin. The change of l-Ala to d-Ala increased the stability of the synthetic C-terminal peptide of sorbin whereas its biological activity, bioavailability, and route of elimination were unchanged. |
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Keywords: | Sorbin Tritium-labeled peptides Pharmacokinetics Clearance Distribution volume Intraperitoneal administration Subcutaneous administration Half-life Mass spectrometry Autoradiography Metabolism Rat Mouse |
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