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

• Published in: European journal of pharmaceutical sciences 2009-12, Vol.38 (5), p.556-563
• Main Authors: Bergström, Christel A S, Bolin, Sara, Artursson, Per, Rönn, Robert, Sandström, Anja
• Format: Article
• Language: English
• Subjects: Acridines - chemistry; Acridines - pharmacokinetics; Acyl sulfonamide; Adenosine Triphosphatases - antagonists & inhibitors; Adenosine Triphosphatases - metabolism; Antiviral Agents - chemistry; Antiviral Agents - pharmacokinetics; ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors; ATP-Binding Cassette, Sub-Family B, Member 1 - physiology; Caco-2; Caco-2 Cells; Cell Membrane Permeability - physiology; Efflux; FARMACI; HCV NS3 protease inhibitors; Humans; Intestinal Absorption - physiology; Membrane permeability; Peptide; Peptides - chemistry; Peptides - pharmacokinetics; Peptides - physiology; PHARMACY; Physicochemical properties; Serine Proteinase Inhibitors - chemistry; Serine Proteinase Inhibitors - pharmacokinetics; Tetrahydroisoquinolines - chemistry; Tetrahydroisoquinolines - pharmacokinetics; Transport rate; Viral Nonstructural Proteins - antagonists & inhibitors; Viral Nonstructural Proteins - metabolism
• ISSN: 0928-0987; 1879-0720; 1879-0720
• DOI: 10.1016/j.ejps.2009.10.004

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.