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In vivo and in vitro methods to dete...

Ghibellini, Giulia.

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In vivo and in vitro methods to determine biliary clearance of drugs in humans.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	In vivo and in vitro methods to determine biliary clearance of drugs in humans./
作者:	Ghibellini, Giulia.
面頁冊數:	284 p.
附註:	Source: Dissertation Abstracts International, Volume: 67-02, Section: B, page: 0832.
Contained By:	Dissertation Abstracts International67-02B.
標題:	Health Sciences, Pharmacology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3207345
ISBN:	9780542545160

In vivo and in vitro methods to determine biliary clearance of drugs in humans.
Ghibellini, Giulia.

In vivo and in vitro methods to determine biliary clearance of drugs in humans. - 284 p.

Source: Dissertation Abstracts International, Volume: 67-02, Section: B, page: 0832.

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

Biliary excretion is an important route of hepatic elimination of drugs and metabolites that is investigated commonly using in vitro or in vivo animal models. However, changes in biliary clearance due to drug-drug interactions, genetic polymorphisms and/or disease state may be species-specific, and animal data may be difficult to extrapolate to humans. This dissertation research focused on the development and refinement of a specialized clinical protocol and novel oroenteric tube to accurately quantify biliary clearance of drugs in humans and the comparison of these values with predicted biliary clearance values determined in sandwich-cultured human hepatocytes. Hepatocytes cultured between two layers of extracellular matrix express and correctly localize functional transport proteins on the canalicular as well as the basolateral domains, and enable determination of drug excretion into bile by quantifying accumulation within the hepatocyte and bile canalicular networks. Experiments were devised and performed to establish the utility of this model to predict hepatobiliary drug disposition in humans. The biliary clearance of three model probes, Tc-99m mebrofenin, Tc-99m sestamibi, and piperacillin, was evaluated in healthy humans. These model compounds exhibited high, intermediate and low biliary clearance, respectively. Pharmacokinetic modeling and simulations of the disposition of Tc-99m mebrofenin in humans, combined with results of in vitro systems transfected with hepatic transport proteins, revealed that disease states and drug interactions would impact the hepatobiliary disposition of this probe. Moreover, the recovery of piperacillin metabolites in bile samples obtained during the clinical studies suggested that the clinical methodology developed is useful for the identification of metabolites unique to the human species. Finally, the biliary clearance values obtained in vivo were compared to those calculated using sandwich-cultured human hepatocytes. The in vitro system proved to be a reliable model for predicting biliary clearance of xenobiotics in humans.

ISBN: 9780542545160Subjects--Topical Terms:

1017717
Health Sciences, Pharmacology.

In vivo and in vitro methods to determine biliary clearance of drugs in humans.
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