title: Correlation between PAMPA permeability and cellular activities of hepatitis C virus protease inhibitors.
abstract: Parallel artificial membrane permeability assay (PAMPA) and Caco-2 cells have been frequently used for the evaluation of in vitro permeability of new chemical entities. In this study we evaluated the correlation between permeability, assessed by both methods, and the cellular potency of 34 novel hepatitis C virus (HCV) protease inhibitors. Two types of assays were used to determine the potency of HCV protease inhibitors: a cell-free assay that evaluates the intrinsic affinity (K(i)) between the protease and the inhibitor and a cell-based replicon assay that determines the inhibitors' IC90. When the K(i)/IC90 ratios were compared with the PAMPA permeability and the Caco-2 permeability by linear regression analysis, a reasonable correlation was found between the K(i)/IC90 ratio and PAMPA permeability (r2=0.76) but not with Caco-2 permeability (r2=0.29). Correlations were also assessed between K(i)/IC90 ratios and the following physico-chemical properties: logP (r2=0.41), logD (r2=0.58), clogP (r2=0.13), and mlogP (r2=0.30). These results suggest that passive permeability may play a role in the uptake and cellular activity of these HCV protease inhibitors, and that PAMPA was more predictive of cellular activity than physico-chemical properties or Caco-2 permeability.
authors.affiliation: Schering-Plough Research Institute, K-15-2-2700, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Cheng
authors.initials: C
authors.lastname: Li
authors.forename: Latha
authors.initials: L
authors.lastname: Nair
authors.forename: Tongtong
authors.initials: T
authors.lastname: Liu
authors.forename: Fangbiao
authors.initials: F
authors.lastname: Li
authors.forename: John
authors.initials: J
authors.lastname: Pichardo
authors.forename: Sony
authors.initials: S
authors.lastname: Agrawal
authors.forename: Robert
authors.initials: R
authors.lastname: Chase
authors.forename: Xiao
authors.initials: X
authors.lastname: Tong
authors.forename: Annette S
authors.initials: AS
authors.lastname: Uss
authors.forename: Stephane
authors.initials: S
authors.lastname: Bogen
authors.forename: F George
authors.initials: FG
authors.lastname: Njoroge
authors.forename: Richard A
authors.initials: RA
authors.lastname: Morrison
authors.forename: K-C
authors.initials: KC
authors.lastname: Cheng
mesh_terms: D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D004058:Diffusion; D016174:Hepacivirus; D006801:Humans; D008567:Membranes, Artificial; D011480:Protease Inhibitors / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors
chemical_list: D008567:Membranes, Artificial; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D017361:Viral Nonstructural Proteins