Compartmental modelling of the pharmacokinetics of a breast cancer resistance protein
Grandjean, Thomas R. B., Chappell, M. J. (Michael J.), Yates, J. W. T., Jones, Kevin, Wood, Gemma and Coleman, Tanya (2011) Compartmental modelling of the pharmacokinetics of a breast cancer resistance protein. Computer Methods and Programs in Biomedicine, Vol.104 (No.2). pp. 81-92. ISSN 0169-2607
WRAP_Chappell_0873262-es-060312-cmpb_tgrandjeanpaper.pdf - Submitted Version - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
Official URL: http://dx.doi.org/10.1016/j.cmpb.2010.08.018
A mathematical model for the pharmacokinetics of Hoechst 33342 following administration into a culture medium containing a population of transfected cells (HEK293 hBCRP) with a potent breast cancer resistance protein inhibitor, Fumitremorgin C (FTC), present is described. FTC is reported to almost completely annul resistance mediated by BCRP in vitro. This non-linear compartmental model has seven macroscopic sub-units, with 14 rate parameters. It describes the relationship between the concentration of Hoechst 33342 and FTC, initially spiked in the medium, and the observed change in fluorescence due to Hoechst 33342 binding to DNA. Structural identifiability analysis has been performed using two methods, one based on the similarity transformation/exhaustive modelling approach and the other based on the differential algebra approach. The analyses demonstrated that all models derived are uniquely identifiable for the experiments/observations available. A kinetic modelling software package, namely FACSIMILE (MPCA Software, UK), was used for parameter fitting and to obtain numerical solutions for the system equations. Model fits gave very good agreement with in vitro data provided by AstraZeneca across a variety of experimental scenarios.
|Item Type:||Submitted Journal Article|
|Subjects:||R Medicine > RM Therapeutics. Pharmacology|
|Divisions:||Faculty of Science > Engineering|
|Library of Congress Subject Headings (LCSH):||Pharmacokinetics -- Mathematical models, Breast -- Cancer -- Effect of drugs on -- Mathematical models, Antineoplastic agents -- Mathematical models|
|Journal or Publication Title:||Computer Methods and Programs in Biomedicine|
|Publisher:||Elsevier Ireland Ltd.|
|Official Date:||November 2011|
|Page Range:||pp. 81-92|
|Access rights to Published version:||Restricted or Subscription Access|
 Doyle LA, Yang W, Abruzzo LV, Krogmann T, Gao Y, Rishi AK and Ross DD (1998) A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc Natl Acad Sci USA 95:15665-15670.
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