title: Hepatitis C virus NS3 protease inhibitors: large, flexible molecules of peptide origin show satisfactory permeability across Caco-2 cells.
abstract: 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.
authors.affiliation: Pharmaceutical Screening and Informatics, Department of Pharmacy, Uppsala University, Uppsala Biomedical Center, P.O. Box 580, SE-751 23 Uppsala, Sweden. christel.bergstrom@farmaci.uu.se
authors.forename: Christel A S
authors.initials: CA
authors.lastname: Bergström
authors.forename: Sara
authors.initials: S
authors.lastname: Bolin
authors.forename: Per
authors.initials: P
authors.lastname: Artursson
authors.forename: Robert
authors.initials: R
authors.lastname: Rönn
authors.forename: Anja
authors.initials: A
authors.lastname: Sandström
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000502:physiology; D000166:Acridines / Q000737:chemistry / Q000493:pharmacokinetics; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000998:Antiviral Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000502:physiology*; D006801:Humans; D007408:Intestinal Absorption / Q000502:physiology*; D010455:Peptides / Q000737:chemistry / Q000493:pharmacokinetics / Q000502:physiology*; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics*; D044005:Tetrahydroisoquinolines / Q000737:chemistry / Q000493:pharmacokinetics; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D000251:Adenosine Triphosphatases; D000998:Antiviral Agents; D010455:Peptides; D015842:Serine Proteinase Inhibitors; D044005:Tetrahydroisoquinolines; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C083501:Elacridar