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Examining the interactive nature of ...

Cummins, Carolyn Louise.

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Examining the interactive nature of cytochrome P450 3A4 and P-glycoprotein in intestinal drug metabolism.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	Examining the interactive nature of cytochrome P450 3A4 and P-glycoprotein in intestinal drug metabolism./
作者:	Cummins, Carolyn Louise.
面頁冊數:	225 p.
附註:	Adviser: Leslie Z. Benet.
Contained By:	Dissertation Abstracts International63-04B.
標題:	Chemistry, Pharmaceutical. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3051039
ISBN:	049365271X

Examining the interactive nature of cytochrome P450 3A4 and P-glycoprotein in intestinal drug metabolism.
Cummins, Carolyn Louise.

Examining the interactive nature of cytochrome P450 3A4 and P-glycoprotein in intestinal drug metabolism. - 225 p.

Adviser: Leslie Z. Benet.

Thesis (Ph.D.)--University of California, San Francisco, 2002.

Biochemical barriers to drug absorption are increasingly being recognized as important determinants in limiting drug availability. Drug efflux by intestinal P-glycoprotein (P-gp) and metabolism by intestinal cytochrome P450 3A4 (CYP3A4) are known to decrease the oral bioavailability of several drugs. The considerable overlap in the substrate selectivity, tissue localization and co-inducibility of CYP3A4 and P-gp has led to the hypothesis that these two proteins work together to coordinate an absorption barrier against xenobiotics. We hypothesized that P-gp could increase intestinal drug metabolism by CYP3A4 through repeated cycles of absorption and efflux. This hypothesis was examined in vitro using CYP3A4-transfected Caco-2 cells and in vivo using the rat single pass intestinal perfusion system. The CYP3A4-transfected Caco-2 cells were characterized for the expression and function of P-gp and CYP3A4 when induced for 24 hours in the presence of cellular inducers sodium butyrate and the phorbol ester, TPA. These conditions provided intact cells with significant CYP3A4 and P-gp expression suitable for the concurrent study of transport and metabolism. The transport, metabolism, and intracellular levels of dual CYP3A4 and P-gp substrates (K77, a novel cysteine protease inhibitor, and rapamycin) and CYP3A4 substrates only (felodipine and midazolam) were measured across CYP3A4-transfected Caco-2 cells in the presence of cyclosporine (inhibitor of CYP3A4 and P-gp) or GG918 (inhibitor of P-gp and not CYP3A4). The extent of metabolism was measured by calculating the extraction ratio across the cells, while accounting for intracellular changes occurring with P-gp inhibition. With these relatively selective substrate/inhibitor studies we discovered that when P-gp alone was inhibited, the extent of metabolism of the dual CYP3A4 and P-gp substrates was decreased but there was no change in the extent of metabolism for the exclusive CYP3A4 substrates. The extent of metabolism for K77 and midazolam was also measured in vivo using the in situ rat intestinal perfusion system with mesenteric cannulation. The fraction metabolized for K77 was decreased in the presence of GG918, but was unchanged for midazolam under similar conditions. These data support the hypothesis and indicate that P-gp, when active, can work in concert with CYP3A4 to modulate intestinal metabolism.

ISBN: 049365271XSubjects--Topical Terms:

550957
Chemistry, Pharmaceutical.

Examining the interactive nature of cytochrome P450 3A4 and P-glycoprotein in intestinal drug metabolism.
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