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Hepatitis C virus N...
Hepatitis C virus NS3 protease inhibitors : large, flexible molecules of peptide origin show satisfactory permeability across Caco-2 cells
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- Bergström, Christel A S (author)
- Uppsala universitet,Institutionen för farmaci
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- Bolin, Sara (author)
- Uppsala universitet,Institutionen för farmaci
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- Artursson, Per (author)
- Uppsala universitet,Institutionen för farmaci
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- Rönn, Robert (author)
- Uppsala universitet,Institutionen för läkemedelskemi
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- Sandström, Anja (author)
- Uppsala universitet,Institutionen för läkemedelskemi
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(creator_code:org_t)
- Elsevier BV, 2009
- 2009
- English.
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In: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 38:5, s. 556-563
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Subject headings
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- The purpose of this study was to investigate the intestinal absorption of tripeptide-based compounds intended for treatment of hepatitis C virus (HCV) infection. The intestinal permeability of 11 HCV NS3 protease inhibitors (Mw 687-841, ClogD(pH 7.4) 1.2-7.3 and 10-13 hydrogen bond donors/acceptors) was measured using Caco-2 cells. Each compound was investigated in the apical to basolateral (a-b) and basolateral to apical (b-a) direction at pH 7.4. For compounds displaying efflux the experiment was repeated in the presence of 1 microM GF120918 to investigate possible involvement of P-glycoprotein (Pgp; ABCB1). All compounds displayed intermediate to high permeability. Seven of them showed extensive efflux, with 31-114-fold higher permeability in the b-a direction than the a-b direction. Addition of the Pgp inhibitor GF120918 reduced the b-a transport rate for the effluxed compounds. However, for inhibitors with a C-terminal carboxylic acid and the acidic bioisosteres thereof the efflux was still significant. Hence, the negative charge resulted in efflux by other ABC-transporters than Pgp. From this study it can be concluded that small changes in the overall structure can lead to a large variation in permeability and efflux as shown by the inhibitors herein, properties that also may influence the resulting inhibition potency of the compounds when performing cell-based pharmacological assays.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
Keyword
- HCV NS3 protease inhibitors
- Acyl sulfonamide
- Peptide
- Caco-2
- Transport rate
- Membrane permeability
- Efflux
- Physicochemical properties
- PHARMACY
- FARMACI
Publication and Content Type
- ref (subject category)
- art (subject category)
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