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Novel mechanisms in the intestinal a...

Bourdet, David Louis.

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Novel mechanisms in the intestinal absorption of hydrophilic cationic drugs.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Novel mechanisms in the intestinal absorption of hydrophilic cationic drugs./
作者:	Bourdet, David Louis.
面頁冊數:	260 p.
附註:	Source: Dissertation Abstracts International, Volume: 66-09, Section: B, page: 4746.
Contained By:	Dissertation Abstracts International66-09B.
標題:	Health Sciences, Pharmacy. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3190223
ISBN:	0542339366

Novel mechanisms in the intestinal absorption of hydrophilic cationic drugs.
Bourdet, David Louis.

Novel mechanisms in the intestinal absorption of hydrophilic cationic drugs. - 260 p.

Source: Dissertation Abstracts International, Volume: 66-09, Section: B, page: 4746.

Thesis (Ph.D.)--The University of North Carolina at Chapel Hill, 2005.

Mechanisms of absorption in the small intestine for hydrophilic organic cations are ill-defined. Many hydrophilic cationic drugs exhibit better absorption in vivo than would be predicted from their physicochemical properties. Studies described in this dissertation provide evidence for novel mechanisms associated with the absorptive transport of the model hydrophilic organic cations, ranitidine and famotidine. The involvement of a combination of drug transport proteins for organic cations and a concentration-dependent paracellular transport mechanism were identified as key mediators of intestinal drug transport for ranitidine and famotidine.

ISBN: 0542339366Subjects--Topical Terms:

1017737
Health Sciences, Pharmacy.

Novel mechanisms in the intestinal absorption of hydrophilic cationic drugs.
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100 1 $a Bourdet, David Louis. $3 1905158
245 1 0 $a Novel mechanisms in the intestinal absorption of hydrophilic cationic drugs.
300 $a 260 p.
500 $a Source: Dissertation Abstracts International, Volume: 66-09, Section: B, page: 4746.
500 $a Adviser: Dhiren R. Thakker.
502 $a Thesis (Ph.D.)--The University of North Carolina at Chapel Hill, 2005.
520 $a Mechanisms of absorption in the small intestine for hydrophilic organic cations are ill-defined. Many hydrophilic cationic drugs exhibit better absorption in vivo than would be predicted from their physicochemical properties. Studies described in this dissertation provide evidence for novel mechanisms associated with the absorptive transport of the model hydrophilic organic cations, ranitidine and famotidine. The involvement of a combination of drug transport proteins for organic cations and a concentration-dependent paracellular transport mechanism were identified as key mediators of intestinal drug transport for ranitidine and famotidine.
520 $a Investigation of the absorptive transport mechanism for ranitidine in Caco-2 cells provided evidence for a saturable, carrier-mediated uptake mechanism at the apical (AP) membrane and a role for P-glycoprotein (P-gp)-mediated efflux in the absorptive transport of ranitidine. The saturable uptake and absorptive transport of ranitidine was inhibited by several organic cation transporter (OCT) substrates and inhibitors including tetraethylammonium (TEA) and 1-methyl-4-phenylpyridinium (MPP+). Ranitidine and famotidine were identified as inhibitors of all three hOCTs, however, were only appreciably transported by hOCT1. Considering the demonstrated AP localization of hOCT1 in Caco-2 cells and human intestinal hOCT1 mRNA expression, hOCT1 likely contributes to intestinal absorption of ranitidine and famotidine. The studies do not rule out a contribution from other unidentified transport proteins or paracellular components that also may participate in the absorption of hydrophilic organic cations. Compartmental kinetic modeling of ranitidine accumulation and transport data in Caco-2 cells supported experimental evidence suggesting the importance of uptake and efflux transport proteins to the absorptive transport of ranitidine, and led to the hypothesis that both a carrier-mediated transcellular pathway and concentration-dependent paracellular pathway contribute to overall absorptive transport of ranitidine. Thus, the studies in this dissertation have identified a novel saturable transcellular transport mechanism for ranitidine absorptive transport, lend support to the hypothesis that paracellular transport may be saturable under some conditions, and illustrate the complexity of intestinal drug transport for hydrophilic organic cations. Collectively, this research has enhanced the knowledge of saturable drug transport mechanisms in the intestine for hydrophilic organic cations and identified putative drug transporters involved in the intestinal absorption of this class of drugs.
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791 $a Ph.D.
792 $a 2005
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