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Prediction of the disposition of a P‐gp substrate in wild‐type and knockout mice tissues: Development of a physiologically based pharmacokinetic (PBPK) model and its global sensitivity analysis
Author(s) -
Fenneteau F.,
Li J.,
Couture L.,
Turgeon J.,
Nekka F.
Publication year - 2007
Publication title -
pamm
Language(s) - English
Resource type - Journals
ISSN - 1617-7061
DOI - 10.1002/pamm.200700608
Subject(s) - physiologically based pharmacokinetic modelling , pharmacokinetics , pharmacology , transporter , disposition , in vivo , p glycoprotein , knockout mouse , biology , chemistry , medicine , biochemistry , receptor , psychology , microbiology and biotechnology , multiple drug resistance , gene , antibiotics , social psychology
In order to improve understanding and prediction of drug disposition prior to in vivo experiments, we aimed to develop a PBPK model that accounts for the involvement of P‐glycoprotein activity and expression in mouse brain, liver, kidney and heart tissues. Model parameters of P‐gp activity and drug diffusion were mainly extrapolated from in vitro data. Model simulations, compared with tissue concentration of 3H‐domperidone intravenously administered toWT and KO mice, suggest the involvement of additional membrane transporters in heart and brain tissues. The global sensitivity analysis showed that the variability of model predictions is related to the variability of the unbound fraction to plasma protein, whereas the uncertainty of the model predictions is associated with the uncertainty of the parameters related to P‐gp genetic expression, and to the activity of additional transporters in heart and brain tissues. (© 2008 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)