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Application of a generic physiologically based pharmacokinetic model to the estimation of xenobiotic levels in rat plasma
Lookup NU author(s)
Professor David Leahy
Author(s)
Brightman FA, Leahy DE, Thomas S, Searle GE
Publication type
Article
Journal
Drug Metabolism and Disposition
Year
2006
Volume
34
Issue
1
Pages
84-93
ISSN (print)
0090-9556
ISSN (electronic)
1521-009X
Full text for this publication is not currently held within this repository. Alternative links are provided below where available.
The routine assessment of xenobiotic in vivo kinetic behavior
is currently dependent upon data obtained through animal experimentation,
although in vitro surrogates for determining key absorption,
distribution, metabolism, and elimination properties are available.
Here we present a unique, generic, physiologically based pharmacokinetic
(PBPK) model and demonstrate its application to the estimation
of rat plasma pharmacokinetics, following intravenous dosing,
from in vitro data alone. The model was parameterized through
an optimization process, using a training set of in vivo data
taken from the literature and validated using a separate test
set of in vivo discovery compound data. On average, the vertical
divergence of the predicted plasma concentrations from the observed
data, on a semilog concentration-time plot, was approximately
0.5 log unit. Around 70% of all the predicted values of a standardized
measure of area under the concentration-time curve (AUC) were
within 3-fold of the observed values, as were over 90% of the
training set
t
1/2
predictions and 60% of those for the test
set; however, there was a tendency to overpredict
t
1/2
for the
test set compounds. The capability of the model to rank compounds
according to a given criterion was also assessed: of the 25%
of the test set compounds ranked by the model as having the
largest values for AUC, 61% were correctly identified. These
validation results lead us to conclude that the generic PBPK
model is potentially a powerful and cost-effective tool for
predicting the mammalian pharmacokinetics of a wide range of
organic compounds, from readily available in vitro inputs only.
Publisher
American Society for Pharmacology and Experimental Therapeutics
URL
http://dx.doi.org/10.1124/dmd.105.004804
DOI
10.1124/dmd.105.004804
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