The internalization of a basic peptide, 001-C8 [H-MeTyr-Arg-MeArg-d-Leu-NH(CH2)8NH2], into enterocyte-like Caco-2 cells was evaluated. Internalization of125I-labeled 001-C8 (125I-001-C8) increased time dependently and reached steady state at 60 min. The steady-state internalization of125I-001-C8 (7.24 ± 0.41 μl/mg protein) was temperature and concentration dependent and was significantly decreased by dansylcadaverine (500 μM), protamine (1 mM), poly-l-lysine (1 mM), E-2078 (1 mM), and ebiratide (1 mM), whereas poly-l-glutamic acid (1 mM), tyrosine (1 mM), and glycylglycine (25 mM) were not inhibitory. Predigestion of acid mucopolysaccharides by heparinase I, heparitinase, and chondroitinase ABC also decreased the internalization. The maximal internalization, the half-saturation constant, and the nonsaturable internalization of125I-001-C8 were 1.13 ± 0.23 pmol/mg protein, 0.47 ± 0.43 μM, and 3.13 ± 0.19 μl/mg protein, respectively. Confocal microscopy also indicated the internalization of fluorescence-derived 001-C8 [001-C8–4-nitrobenz-2-oxa-1,3-diazole (001-C8-NBD)]. Granular staining seen within the cell, excluding nuclei, indicated the sequestration of 001-C8-NBD within endocytotic vesicles. Dansylcadaverine and protamine strongly decreased the granular distribution of 001-C8-NBD within the cell. These results demonstrate that 001-C8 is taken up by Caco-2 cells via adsorptive-mediated endocytosis.

01 Nov 1997·Journal of Pharmacy and PharmacologyQ3 · MEDICINE

Effects of Different Absorption Enhancers on the Permeation of Ebiratide, an ACTH Analogue, across Intestinal Membranes

Q3 · MEDICINE

Article

Author: Okagawa, Taishi ; Yamamoto, Akira ; Kondo, Shuji ; Uchiyama, Tomomi ; Shimura, Takesada ; Muranishi, Shozo ; Kotani, Atsushi ; Tabata, Shigeru

AbstractThe permeation of ebiratide (H-Met(O2)-Glu-His-Phe-d-Lys-Phe-NH(CH2)8NH2), a novel ACTH analogue, across the intestinal mucosae has been examined by use of isolated intestinal membranes from rats in a modified Ussing chamber.Regional differences were observed in the permeation of ebiratide across intestinal membranes; the order of membrane permeability was jejunum > ileum > duodenum > colon. Overall, the permeation of ebiratide was relatively poor. The effects of various absorption enhancers were examined to increase the intestinal permeability to ebiratide. Sodium glycocholate and sodium caprate had no significant enhancing effect on the permeability of the jejunal membrane, but significantly enhanced the permeation of ebiratide through the colonic membrane. On the other hand, N-dodecyl-β-d-maltopyramoside (LM) significantly enhanced the permeation of ebiratide through both jejunal and colonic membranes. In general, the absorption-enhancing effects of these agents were more predominant in the colon than in the jejunum. Membrane damage by the absorption enhancers was evaluated by measuring the amount of protein released from the intestinal membrane. It was found that all the absorption enhancers slightly increased the amount of protein released, but that the amounts of protein released in the presence of these enhancers were much less than in the presence of ethylenediaminetetraacetic acid (EDTA), used as a positive control.These findings suggest that the absorption enhancers, especially LM might be useful adjuvants for improving the intestinal absorption of peptide and protein drugs, including ebiratide.

01 Aug 1997·Experimental NeurologyQ2 · MEDICINE

Blood–Brain Barrier Permeability to Ebiratide and TNF in Acute Spinal Cord Injury

Q2 · MEDICINE

Article

Author: Abba J. Kastin ; William A. Banks ; Weihong Pan

Spinal cord injury (SCI) in mammals has a poor outcome because of a lack of regeneration. Alteration of the local environment after injury may induce regeneration. However, the passage of blood-borne or exogenous neurotrophic substances through the blood-brain barrier (BBB) is not well characterized in either normal or injured states. We investigated the permeability of the BBB in normal and injured states to two markers of permeability (albumin and sucrose), to a peptide (ebiratide), and to a cytokine [tumor necrosis factor-alpha(TNF)]. We found that in normal mice the cervical and lumbar areas of the spinal cord were more permeable than the thoracic area and the brain to all four substances. The penetration of the alpha-MSH/ACTH analogue ebiratide and of TNF, substances that have saturable transport systems across the BBB and may be involved in regenerative processes in the CNS, followed a regional pattern of differential permeability comparable to that of albumin and sucrose. Complete transection at the lumbar level induced a temporal change in the permeability of the BBB. The increased permeability, as measured by the radioactively labeled tracers albumin and sucrose, was most apparent in the lumbar region proximal to the transection. After SCI, the permeability to ebiratide remained unchanged, suggesting that disruption of the BBB did not affect the transport system for ebiratide. By contrast, the increase of permeability to TNF exceeded that detected by the markers albumin and sucrose. This enhanced permeability was inhibited by excess unlabeled TNF in the blood, showing saturability. This suggests that the transport system for TNF may be activated in SCI.

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