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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 /

Record Type:	Electronic resources : Monograph/item
Title/Author:	The roles of multiple transporters in the intestinal abosrption of saquinavir, a peptidomimetic HIV protease inhibitor // Gregory Charles Williams.
Author:	Williams, Gregory Charles,
Description:	1 electronic resource (205 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 64-04, Section: B.
Contained By:	Dissertations Abstracts International64-04B.
Subject:	Pharmaceuticals. -
Online resource:	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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100 1 $a Williams, Gregory Charles, $e author. $3 3826752
245 1 0 $a The roles of multiple transporters in the intestinal abosrption of saquinavir, a peptidomimetic HIV protease inhibitor / $c Gregory Charles Williams.
264 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2002
300 $a 1 electronic resource (205 pages)
336 $a text $b txt $2 rdacontent
337 $a computer $b c $2 rdamedia
338 $a online resource $b cr $2 rdacarrier
500 $a Source: Dissertations Abstracts International, Volume: 64-04, Section: B.
500 $a Publisher info.: Dissertation/Thesis.
500 $a Advisors: Sinko, Patrick J.
502 $b Ph.D. $c Rutgers The State University of New Jersey, School of Graduate Studies $d 2002.
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.
546 $a English
590 $a School code: 0190
650 4 $a Pharmaceuticals. $3 3562593
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
690 $a 0572
690 $a 0490
690 $a 0719
710 2 $a Rutgers The State University of New Jersey, School of Graduate Studies. $e degree granting institution. $3 3765896
720 1 $a Sinko, Patrick J. $e degree supervisor.
773 0 $t Dissertations Abstracts International $g 64-04B.
790 $a 0190
791 $a Ph.D.
792 $a 2002
856 4 0 $u https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3055101