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Novel approaches to assess the effic...

Tippin, Timothy Kent.

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Novel approaches to assess the efficacy and toxicity of intestinal absorption enhancers.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Novel approaches to assess the efficacy and toxicity of intestinal absorption enhancers./
作者:	Tippin, Timothy Kent.
面頁冊數:	238 p.
附註:	Source: Dissertation Abstracts International, Volume: 67-10, Section: B, page: 5770.
Contained By:	Dissertation Abstracts International67-10B.
標題:	Chemistry, Pharmaceutical. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3239270
ISBN:	9780542941290

Novel approaches to assess the efficacy and toxicity of intestinal absorption enhancers.
Tippin, Timothy Kent.

Novel approaches to assess the efficacy and toxicity of intestinal absorption enhancers. - 238 p.

Source: Dissertation Abstracts International, Volume: 67-10, Section: B, page: 5770.

Thesis (Ph.D.)--The University of North Carolina at Chapel Hill, 2006.

Hydrophilic molecules do not easily cross the intestinal epithelium. One approach to improve intestinal absorption of hydrophilic compounds is to reversibly-modulate tight junctions by co-administration of a paracellular permeability enhancer (PPE). Currently, there is no enhancer that has shown sufficient potency or sufficiently low toxicity to be used for this purpose in humans.

ISBN: 9780542941290Subjects--Topical Terms:

550957
Chemistry, Pharmaceutical.

Novel approaches to assess the efficacy and toxicity of intestinal absorption enhancers.
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245 1 0 $a Novel approaches to assess the efficacy and toxicity of intestinal absorption enhancers.
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500 $a Source: Dissertation Abstracts International, Volume: 67-10, Section: B, page: 5770.
500 $a Adviser: Dhiren R. Thakker.
502 $a Thesis (Ph.D.)--The University of North Carolina at Chapel Hill, 2006.
520 $a Hydrophilic molecules do not easily cross the intestinal epithelium. One approach to improve intestinal absorption of hydrophilic compounds is to reversibly-modulate tight junctions by co-administration of a paracellular permeability enhancer (PPE). Currently, there is no enhancer that has shown sufficient potency or sufficiently low toxicity to be used for this purpose in humans.
520 $a The potency of PPEs is routinely assessed in vitro using cell monolayers. However, in vitro potency determinations typically underestimate the concentrations of PPEs that are required to improve the intestinal absorption of hydrophilic compounds in animals. Studies in this work demonstrated that components present in intestinal fluid, when introduced to cell monolayers, substantially reduced the potency of amphiphilic PPEs by sequestration in mixed micelles of intestinal fluid. Addition of serum on the basolateral side, to simulate the presence of blood components on the serosal side of the intestinal epithelium, had only a modest impact on PPE potency.
520 $a Agitation of cell monolayers, representing intestinal motility, increased the apparent potency of amphiphilic PPEs, by reducing the height of the unstirred water layer. Therefore, incorporation of (1) components of intestinal fluid and (2) features of intestinal motility into the cell culture model are recommended for improved predictivity of PPE potency. Amajor concern affecting the use of PPEs in humans is that theymay increase the risk of systemic exposure of toxins, though this has not been studied directly. In this work, the model amphiphilic PPE, hexadecylphosphocholine, was found to increase the in vitro flux of lipopolysaccharide across Caco-2 cells, but only at relatively toxic concentrations, as measured by a novel quantitative histological technique. After transient intestinal administration of the minimum effective dose of hexadecylphosphocholine to rats, marked intestinal damage was observed, but no evidence for systemic absorption of lipopolysaccharide was found. These studies provide evidence that even at high doses of PPEs that might cause some intestinal damage, significant amounts of lipopolysaccharide are not absorbed. The results obtained in this study challenge the current dogma that intestinal absorption enhancers are likely to cause systemic exposure to microbial toxins and resultant toxicity by compromising the intestinal epithelial barrier.
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791 $a Ph.D.
792 $a 2006
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