Hepatitis C virus NS3 protease inhibitors: Large, flexible molecules of peptide origin show satisfactory permeability across Caco-2 cells

Christel A S Bergström, Sara Bolin, Per Artursson, Robert Rönn, Anja Sandström

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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, C log DpH 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 μM 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.

Original languageEnglish
Pages (from-to)556-563
Number of pages8
JournalEuropean Journal of Pharmaceutical Sciences
Issue number5
Publication statusPublished - 8 Dec 2009
Externally publishedYes


  • Acyl sulfonamide
  • Caco-2
  • Efflux
  • HCV NS3 protease inhibitors
  • Membrane permeability
  • Peptide
  • Physicochemical properties
  • Transport rate

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