Use of Protease Inhibitors to Improve Calcitonin Absorption from the Small and Large Intestine in Rats

Tozaki, Hideyuki; Odoriba, Tomokazu; Iseki, Tomoya; Taniguchi, Tetsuo; Fujita, Takuya; Murakami, Masahirô; Muranishi, Shozo; Yamamoto, Akira

doi:10.1111/j.2042-7158.1998.tb04008.x

Cited by 39 publications

(25 citation statements)

References 52 publications

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“…The greatest insulin absorption from the ileum might reflect differences in proteolytic activity along the intestine. Insulin degradation was much greater in the duodenum and jejunum than in the ileum because the protease content is much higher in the upper small intestine than in the descending small intestine (36). The ranking order for the total different endopeptidase activity in gut luminal fluids and exopeptidase activity in gut mucosal homogenates of rats was jejunum> ileum>colon.…”

Section: Discussionmentioning

confidence: 92%

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: 92%

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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“…The nasal absorption of calcitonin was estimated by measuring the plasma calcium levels, as reported previously Tozaki et al, 1998Tozaki et al, , 2001Fetih et al, 2006). The plasma calcium levels after calcitonin administration were determined by Calcium E Test (Wako Pure Chemical Industries, Osaka, Japan).…”

Section: Methodsmentioning

confidence: 99%

Effects of polyamidoamine (PAMAM) dendrimers on the nasal absorption of poorly absorbable drugs in rats

Dong

Katsumi

Sakane

et al. 2010

International Journal of Pharmaceutics

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“…[23][24][25] Male Wistar rats (250-300 g) were fasted overnight and anesthetized with sodium pentobarbital (32 mg/kg body weight i.p.). The intestine was exposed through the midline abdominal incision.…”

Section: Transport Of Rhodamine123 Across the Intestinal Membranes Bymentioning

confidence: 99%

Effects of Labrasol and Other Pharmaceutical Excipients on the Intestinal Transport and Absorption of Rhodamine123, a P-Glycoprotein Substrate, in Rats

Yang

Shen

Katsumi

et al. 2007

Biological & Pharmaceutical Bulletin

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103

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P-Glycoprotein (P-gp) is a plasma membrane glycoprotein of about 170 kDa that belongs to the superfamily of ATPbinding cassette (ABC) transporters. P-gp is extensively expressed in tumor cells, liver, intestinal brush border membranes, kidney, brain, and adrenal glands.1) It can actively pump drugs out of cells, thus reducing the oral bioavailability of a wide range of drugs such as digoxin, vinca alkaloids, and b-adrenergic agonists.It has been reported that some P-glycoprotein inhibitors such as verapamil and cyclosporin A could enhance the bioavailability of P-gp substrate drugs.2-4) But it is well known that these drugs themselves have pharmacological activities. Therefore, it is important to find a P-gp inhibitor which does not have pharmacological activities. It has been demonstrated that a number of excipients could inhibit the function of P-gp, thereby increasing the absorption of P-gp substrate drugs. 5) These excipients include polyethylene glycols (PEGs), nonionic surfactants, fatty acids and bile salts. [6][7][8][9][10][11][12][13][14][15][16] It has been reported that several excipients such as Cremophor EL, Tween 80, n-lauryl-b-D-maltopyranoside (LM), Pluronic P85, vitamin E-TPGS, PEGs, sodium caprate and dimethyl-b-cyclodextrin could inhibit the function of Pgp by in vitro and in vivo methods. [6][7][8][9][10][11][12][13][14][15][16] Among these pharmaceutical excipients, Labrasol is one which has been widely used for the solubilization of hydrophobic drugs.17) Labrasol is obtained from coconut oil and has very low toxicity with an LD 50 of 22 g/kg for rats. Recently, it was reported that Labrasol had a strong absorption enhancing effect and that intestinal absorption of various poorly absorbable drugs including gentamicin, insulin and vancomycin was enhanced in its presence. [18][19][20] However, few studies examined the effect of Labrasol on the function of P-gp in the intestine and the intestinal absorption of P-gp substrates. Cornaire et al. (2004) examined the effect of Labrasol on the transport of digoxin by an in vitro everted sac experiment, and reported that 0.5% Labrasol increased the transport of digoxin in this experiment.21) However, they demonstrated that 0.5% Labrasol could increase the lactate dehydrogenase (LDH), and so the increase in digoxin transport might be due to the intestinal membrane damage, and not to the inhibition of P-gp function in the intestine. Furthermore, they did not study the different regional effects of Labrasol on the transport of P-gp substrate and in situ or in vivo intestinal absorption of P-gp substrate with or without Labrasol.In this study, therefore, we studied the effect of Labrasol on the function of P-gp using two different intestinal absorption experiments. We first adopted an in vitro diffusion chamber system using the isolated rat intestinal membrane to evaluate the effects of Labrasol and other pharmaceutical excipients, Gelucire44/14 and Transcutol P on the intestinal transport of rhodamine123, a P-gp substrate. In addition, the intestinal mem...

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Use of Protease Inhibitors to Improve Calcitonin Absorption from the Small and Large Intestine in Rats

Cited by 39 publications

References 52 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

Effects of polyamidoamine (PAMAM) dendrimers on the nasal absorption of poorly absorbable drugs in rats

Effects of Labrasol and Other Pharmaceutical Excipients on the Intestinal Transport and Absorption of Rhodamine123, a P-Glycoprotein Substrate, in Rats

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