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The roles of multiple transporters i...

Williams, Gregory Charles,

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The roles of multiple transporters in the intestinal abosrption of saquinavir, a peptidomimetic HIV protease inhibitor /

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	The roles of multiple transporters in the intestinal abosrption of saquinavir, a peptidomimetic HIV protease inhibitor // Gregory Charles Williams.
作者:	Williams, Gregory Charles,
面頁冊數:	1 electronic resource (205 pages)
附註:	Source: Dissertations Abstracts International, Volume: 64-04, Section: B.
Contained By:	Dissertations Abstracts International64-04B.
標題:	Pharmaceuticals. -
電子資源:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3055101
ISBN:	9780493703848

The roles of multiple transporters in the intestinal abosrption of saquinavir, a peptidomimetic HIV protease inhibitor /
Williams, Gregory Charles,

The roles of multiple transporters in the intestinal abosrption of saquinavir, a peptidomimetic HIV protease inhibitor /Gregory Charles Williams. - 1 electronic resource (205 pages)

Source: Dissertations Abstracts International, Volume: 64-04, Section: B.

The contributions of human multidrug resistance-associated protein 1 (hMRP1), multidrug resistance-associated protein 2 (hMRP2) and P-glycoprotein (hPgp) to saquinavir transport were investigated using MDCKII cells overexpressing hMRP 1 (MDCKII-MRP1), hMRP2 (MDCKII-MRP2) or hPgp (MDCKII-PGP) in comparison with MDCKII/wild type (MDCKII/wt) cells. Saquinavir transport and cytotoxicity were measured. The effects of GF120918 (specific Pgp inhibitor) and MK-571 (MRP family inhibitor) were determined. To develop a standard protocol for MDCKII cell studies, the effects of seeding density and substratum on saquinavir transport through, and interactions with MDCKII-PGP cell monolayers were investigated. Saquinavir presence significantly disrupted MDCKII-PGP monolayer integrity. To minimize monolayer disruption, all cell lines were seeded with 5 x 104 cells/cm 2 on collagen-coated polycarbonate membranes. Collagen-coating increased Pgp expression and saquinavir efflux ratios (ratios of BL to AP/AP to BL permeability) correlated with Pgp expression in this rank order: MDCKII-PGP (on collagen-coated polycarbonate) > MDCKII-PGP (on polycarbonate) > MDCKII/wt (on collagen-coated polycarbonate). For MDCKII-PGP cells, GF120918 reduced saquinavir efflux ratios but did not fully inhibit saquinavir efflux. Saquinavir efflux was fully inhibited, in a concentration dependent manner, by MK-571 in the presence GF120918. The MDCKII-MRP1 (LD50 = 10.5 μM), MDCKII-MRP2 (LD50 = 27.1 μM) and MDCKII-PGP (LD50 = 33.7 μM) cell lines exhibited statistically greater viability than the MDCKII/wt cells (LD50 = 7.8 μM). Relative to the MDCKII/wt, the MDCKII-MRP1 cells had a significantly reduced saquinavir efflux ratio due to basolaterally directed transport by hMRP1 competing with apically directed endogenous cMRP2. The MDCKII-MRP2 cells had a significantly increased saquinavir efflux ratio due to apically directed transport by hMRP2. To influence specific basolateral or apical transport events in association with the known localization of hMRP1 and hMRP2, MK-571 was selectively applied with saquinavir to apical or basolateral surfaces of MDCKII-MRP1, MDCKII-MRP2 or MDCKII/wt monolayers. Only basolateral application of MK-571 to MDCKII/wt and MDCKII-MRP1 monolayers significantly reduced saquinavir efflux ratios, causing increased AP to BL transport. Collectively, these results indicate saquinavir transport by at least hMRP1, human and canine MRP2, and human and canine Pgp. These results further suggest saquinavir transport by an unidentified MK-571 sensitive BL to AP transport mechanism with basolateral localization.

English

ISBN: 9780493703848Subjects--Topical Terms:

3562593
Pharmaceuticals.
Subjects--Index Terms:

HIV protease inhibitor

The roles of multiple transporters in the intestinal abosrption of saquinavir, a peptidomimetic HIV protease inhibitor /
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520 $a The contributions of human multidrug resistance-associated protein 1 (hMRP1), multidrug resistance-associated protein 2 (hMRP2) and P-glycoprotein (hPgp) to saquinavir transport were investigated using MDCKII cells overexpressing hMRP 1 (MDCKII-MRP1), hMRP2 (MDCKII-MRP2) or hPgp (MDCKII-PGP) in comparison with MDCKII/wild type (MDCKII/wt) cells. Saquinavir transport and cytotoxicity were measured. The effects of GF120918 (specific Pgp inhibitor) and MK-571 (MRP family inhibitor) were determined. To develop a standard protocol for MDCKII cell studies, the effects of seeding density and substratum on saquinavir transport through, and interactions with MDCKII-PGP cell monolayers were investigated. Saquinavir presence significantly disrupted MDCKII-PGP monolayer integrity. To minimize monolayer disruption, all cell lines were seeded with 5 x 104 cells/cm 2 on collagen-coated polycarbonate membranes. Collagen-coating increased Pgp expression and saquinavir efflux ratios (ratios of BL to AP/AP to BL permeability) correlated with Pgp expression in this rank order: MDCKII-PGP (on collagen-coated polycarbonate) > MDCKII-PGP (on polycarbonate) > MDCKII/wt (on collagen-coated polycarbonate). For MDCKII-PGP cells, GF120918 reduced saquinavir efflux ratios but did not fully inhibit saquinavir efflux. Saquinavir efflux was fully inhibited, in a concentration dependent manner, by MK-571 in the presence GF120918. The MDCKII-MRP1 (LD50 = 10.5 μM), MDCKII-MRP2 (LD50 = 27.1 μM) and MDCKII-PGP (LD50 = 33.7 μM) cell lines exhibited statistically greater viability than the MDCKII/wt cells (LD50 = 7.8 μM). Relative to the MDCKII/wt, the MDCKII-MRP1 cells had a significantly reduced saquinavir efflux ratio due to basolaterally directed transport by hMRP1 competing with apically directed endogenous cMRP2. The MDCKII-MRP2 cells had a significantly increased saquinavir efflux ratio due to apically directed transport by hMRP2. To influence specific basolateral or apical transport events in association with the known localization of hMRP1 and hMRP2, MK-571 was selectively applied with saquinavir to apical or basolateral surfaces of MDCKII-MRP1, MDCKII-MRP2 or MDCKII/wt monolayers. Only basolateral application of MK-571 to MDCKII/wt and MDCKII-MRP1 monolayers significantly reduced saquinavir efflux ratios, causing increased AP to BL transport. Collectively, these results indicate saquinavir transport by at least hMRP1, human and canine MRP2, and human and canine Pgp. These results further suggest saquinavir transport by an unidentified MK-571 sensitive BL to AP transport mechanism with basolateral localization.
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650 4 $a Pharmacology. $3 634543
650 4 $a Anatomy & physiology. $3 3434423
650 4 $a Animals. $2 fast $3 518809
653 $a HIV protease inhibitor
653 $a Immune deficiency
653 $a Intestinal abosrption
653 $a Peptidomimetic
653 $a Saquinavir
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791 $a Ph.D.
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