Region-Dependent Role of the Mucous/Glycocalyx Layers in Insulin Permeation Across Rat Small Intestinal Membrane

Aoki, Y.; Morishita, Mariko; Asai, Kazunori; Akikusa, Bunshiro; Hosoda, S; Takayama, Kozo

doi:10.1007/s11095-005-6137-z

Cited by 60 publications

(35 citation statements)

References 29 publications

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“…The mucus/glycocalyx layers presumably also provide an enzymatic barrier and/or diffusional barrier. The enzymatic degradation of insulin in the mucus/glycocalyx layers tends to increase toward the upper small intestine in the following order: duodenum>jejunum>ileum (38). By contrast, the colonic coadministration of insulin and penetratin had a smaller effect on increasing insulin absorption, even though the proteolytic activity in the colon may be much lower than that in the small intestine (39).…”

Section: Discussionmentioning

confidence: 97%

Region-Dependent Role of Cell-Penetrating Peptides in Insulin Absorption Across the Rat Small Intestinal Membrane

Khafagy

Iwamae

Kamei

et al. 2015

AAPS J

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Abstract. We have reported that the cell-penetrating peptide (CPP) penetratin acts as a potential absorption enhancer in oral insulin delivery systems and that this action occurs through noncovalent intermolecular interactions. However, the region-dependent role of CPPs in intestinal insulin absorption has not been clarified. To identify the intestinal region where CPPs have the most effect in increasing insulin absorption, the region-dependent action of penetratin was investigated using in situ closed intestinal loops in rats. The order of the insulin area under the insulin concentration-time curve (AUC) increase effect by L-penetratin was ileum>jejunum>duodenum>colon. By contrast, the AUC order after coadministration of insulin with D-penetratin was colon>duodenum≥jejunum and ileum. We also compared the effects of the L-and D-forms of penetratin, R8, and PenetraMax on ileal insulin absorption. Along with the CPPs used in this study, L-and D-PenetraMax produced the largest insulin AUCs. An absorption study using ilea pretreated with CPPs showed that PenetraMax had no irreversible effect on the intestinal epithelial membrane. The degradation of insulin in the presence of CPPs was assessed in rat intestinal enzymatic fluid. The half-life (t 1/2 ) of insulin increased from 14.5 to 23.7 and 184.7 min in the presence of L-and D-PenetraMax, respectively. These enzymatic degradation-resistant effects might contribute partly to the increased ileal absorption of insulin induced by D-PenetraMax. In conclusion, this study demonstrated that the ability of the L-and D-forms of penetratin to increase intestinal insulin absorption was maximal in the ileum and the colon, respectively, and that D-PenetraMax is a powerful but transient enhancer of oral insulin absorption.

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Section: Discussionmentioning

confidence: 97%

Region-Dependent Role of Cell-Penetrating Peptides in Insulin Absorption Across the Rat Small Intestinal Membrane

Khafagy

Iwamae

Kamei

et al. 2015

AAPS J

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“…21,22) Hence, the effect of PLA may also be influenced by the enzymes in the mucous layer. 20) The highest F 0-4 h was obtained in the jejunum when aprotinin was co-administered with PLA. In contrast, the absorption of FD-4 was not observed to increase after the co-administering aprotinin in the colon, and the F 0-4 h was almost equal to that when only 0.5% PLA was combined with FD-4.…”

Section: Methodsmentioning

confidence: 94%

“…Meanwhile, the T max was not changed by co-administration of aprotinin in the ileum, indicating that the protease has a little influence on the enhancing effect of PLA, that is, only a little protease might exist in the ileum compared with the duodenum and jejunum. 20) The mucous layer seems to be removed incompletely in a well-established in situ closed-loop method. It has been reported that the pancreatic enzymes capable of degrading proteins resided in the mucous layer.…”

Section: Methodsmentioning

confidence: 99%

Effect of Poly-<small>L</small>-arginine on Intestinal Absorption of Hydrophilic Macromolecules in Rats

Yamaki

Uchida

Kuwahara

et al. 2013

Biological & Pharmaceutical Bulletin

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We have already reported that poly-l-arginine (PLA) remarkably enhanced the in vivo nasal absorption of hydrophilic macromolecules without producing any significant epithelial damage in rats. In the present study, we examined whether PLA could enhance the absorption of a model hydrophilic macromolecule, fluorescein isothiocyanate-dextran (FD-4), across the intestinal mucosa, as well as the nasal mucosa, by an in situ closed-loop method using the rat intestine. PLA was found to enhance the intestinal absorption of FD-4 in a concentration-dependent manner within the concentrations investigated in this study, but segment-specific differences were found to be associated with this effect (ileum>jejunum>duodenum≧colon). The factors responsible for the segment-specific differences were also investigated by intestinal absorption studies using aprotinin, a trypsin inhibitor, and an analysis of the expression of occludin, a tight junction protein. In the small intestine, the differences in the effect of PLA on the absorption of FD-4 may be related to the enzymatic degradation of PLA. In the colon, the reduced effect of PLA on the absorption of FD-4 may be related to the smaller surface area for absorption and the higher expression of occludin compared with other segments.Key words poly-l-arginine; intestinal absorption; enhancer; fluorescein isothiocyanate-dextran (FD-4); occludin; aprotininWe have already reported that poly-l-arginine (PLA), a polycation, remarkably enhanced the in vivo nasal absorption of hydrophilic macromolecules in rats and increased their in vitro permeation across the rabbit nasal epithelium without producing any significant epithelial damage. [1][2][3][4][5] This effect is caused by the opening of tight junctions (TJ) in the epithelial cells. PLA plays an important role in opening the TJ in these cells, and the reaction induced by PLA appears to be reversible.4,6) Therefore, PLA is considered to be promising as an absorption enhancer for transnasal drug delivery. Although some studies have examined whether PLA can also enhance the absorption of hydrophilic macromolecules across the nasal epithelium, conjunctiva, alveolar epithelium, and Caco-2 cell sheets, [7][8][9][10] there have been no studies looking at PLA᾿s absorption enhancing effect across the intestinal mucosa. The intestinal mucosa is an important tissue particularly for the absorption of orally administered drugs.The intestinal absorption of hydrophilic macromolecules is well known to be typically very poor.11) The small intestine has an extensive surface area for absorption, but various digestive enzymes exist in the gastrointestinal tract. The property of intestinal mucosa differs from that of the nasal mucosa in some respects. Therefore, in order to improve the absorption of hydrophilic macromolecules, various strategies such as the use of absorption enhancers, protease inhibitors and chemical modification have been examined in the intestinal mucosa as well as the nasal mucosa. [12][13][14][15] It was recently reported that the TJ ba...

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“…The calcium ion was knows as the activator of enzymatic activity related to the insulin degradation in the intestine (Yamagata et al, 2006;Madsen and Peppas, 1999). The insulin degradation is one of major barriers for the insulin permeation through the intestinal mucosa (Aoki et al, 2005), and the inhibitory effect of insulin degradation would play a crucial role for the enhancing effect of insulin absorption by the polymers.…”

Section: Discussionmentioning

confidence: 99%

Key functions in polymer carriers for intestinal absorption of insulin

Nakamura

Morishita

Ehara

et al. 2008

International Journal of Pharmaceutics

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This work aimed to clarify the relationship between polymer function and insulin absorption, and to evaluate the optimized preparative formulation predicted from this relationship.Insulin-loaded polymer (ILP) carrier systems were prepared following a two-factor composite second-order spherical experimental design. To investigate the polymer function, we evaluated its insulin release, bioadhesiveness, and protective effect. Each ILP was administered intestinally, and glucose reduction was monitored as the pharmacological effect. Based on these data, an optimized formulation was predicted and how the polymer function affects insulin absorption was clarified by multivariate spline (MVS) interpolation.A greater pharmacological effect was apparent in ILPs with a smaller particle size and loaded with more insulin. The pharmacological effect predicted by MVS after the administration of ILP made under optimized preparative conditions was almost identical to the observed effect. Moreover, MVS clarified the relationship between the polymer function and the pharmacological effect. These results supported that MVS can be an effective tool with which to approximate the relationship between the function of a dosage form and its absorption, and to explore the optimized preparative conditions.

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Region-Dependent Role of the Mucous/Glycocalyx Layers in Insulin Permeation Across Rat Small Intestinal Membrane

Cited by 60 publications

References 29 publications

Region-Dependent Role of Cell-Penetrating Peptides in Insulin Absorption Across the Rat Small Intestinal Membrane

Region-Dependent Role of Cell-Penetrating Peptides in Insulin Absorption Across the Rat Small Intestinal Membrane

Effect of Poly-<small>L</small>-arginine on Intestinal Absorption of Hydrophilic Macromolecules in Rats

Key functions in polymer carriers for intestinal absorption of insulin

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