Here - Stiftung Forschung 3R

Table 3. Selected parameters for the multiparametric assessment of toxic compounds.
tion and gene expression induction relative
to the culture protocol, the LD cells
showing a more homogeneous and stronger
toxic response. These results indicate
the importance of the maintenance protocol
on the physiological response of the
cells. The HD and LD differentiated cells
displayed a number of morphological and
physiological differences that must be taken
in account when these cells are used as
an intestinal model.
In Silico Modelling
The in silico modelling activities (partners
UM, Symcyp, and SiBi) relating to objective
4, resulted in a tiered approach for the
assessment of the pharmacokinetic models.
Four levels were proposed, which were
relevant to both the selection of probe
compounds and the conduct of the appropriate
experiment that would allow evaluation.
Different systems were deemed appropriate
for different purposes (hence
the need for different levels of evaluation).
The objective of the first level was to triage
novel systems based on existing information
generated using whatever methods
are currently available in their own laboratories.
At the second level, metabolic and
transporter competence and cellular integrity
were assessed qualitatively. It was
expected that at the third level, full kinetic
studies would be performed using specific
probes under standard conditions of
linearity. The fourth level represented the
most detailed level of evaluation involving
several model compounds that had in vivo
correlates available to be used in the assessment.
A list of compounds has been worked out
both for permeability and for metabolism
parameters. State-of-the-art models such
as human cryopreserved hepatocyte were
compared with a new model developed in
the project: differentiated HepaRG cryopreserved
cells.
Three lists of model compounds (each 30-
50 drugs) for intestinal permeability, hepatic
and intestinal metabolism were collated
from the literature. The choice covered
a wide range of: permeability/metabolic
clearance values, physico-chemical
properties and transport mechanism/
enzyme involvement. In addition a much
shorter list of ‘first choice’ drugs (calibrators)
for metabolic study was also provided.
Models for prediction of intestinal
permeability, hepatic clearance and Fg
(fraction escaping first pass metabolism
PROGRESS REPORTS FROM EU-FUNDED PROJECTS
Progress Report 2011 & AXLR8-2 Workshop Report
111