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Intestinal barriers to oral bioavail...

Zhu, Li.

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Intestinal barriers to oral bioavailability: Saquinavir as a model compound.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	Intestinal barriers to oral bioavailability: Saquinavir as a model compound./
作者:	Zhu, Li.
面頁冊數:	165 p.
附註:	Adviser: Win L. Chiou.
Contained By:	Dissertation Abstracts International67-05B.
標題:	Health Sciences, Pharmacology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3218803
ISBN:	9780542701900

Intestinal barriers to oral bioavailability: Saquinavir as a model compound.
Zhu, Li.

Intestinal barriers to oral bioavailability: Saquinavir as a model compound. - 165 p.

Adviser: Win L. Chiou.

Thesis (Ph.D.)--University of Illinois at Chicago, Health Sciences Center, 2006.

Saquinavir is a peptidomimetic inhibitor of the HIV protease enzyme and was the first member of its class to become clinically available for the treatment of HIV infection. However, clinical use of the drug is severely hampered by its poor pharmacokinetic properties, in particular, the low and variable bioavailability. In recent years, intestinal first-pass metabolism mediated by CYP3A4 and efflux transport mediated by P-gp have been recognized as important determinants to oral drug absorption and bioavailability. In this study, using saquinavir, dual substrate of both CYP3A4 and P-gp, as a model compound and with the aid of an assortment of absorption models, including brush border membrane vesicles, caco-2 cell monolayers, Ussing chambers, closed loop with mesenteric vein cannulation and portal and jugular vein cannulated rats, we investigated the various biochemical barriers to the intestinal absorption and bioavailability. Our results show that cellular accumulation, an often neglected factor in absorption studies, was an important rate-limiting factor to the transcellular transport of saquinavir. Efflux transport, especially that mediated by P-gp, was shown to exert a significant barrier effect to saquinavir's absorption at the intestinal level. More importantly, data from our studies demonstrate that P-gp inhibition in the intestine significantly promotes intracellular metabolism mediated by CYP3A4. The role of cellular accumulation in influencing the interaction between intestinal efflux and metabolism was discussed and a compensatory mode of interaction was proposed, subsequently tested and verified in in vitro, in situ and in vivo systems.

ISBN: 9780542701900Subjects--Topical Terms:

1017717
Health Sciences, Pharmacology.

Intestinal barriers to oral bioavailability: Saquinavir as a model compound.
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