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Compartmental modelling of the pharmacokinetics of a breast cancer resistance protein
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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. doi:10.1016/j.cmpb.2010.08.018
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WRAP_Chappell_0873262-es-060312-cmpb_tgrandjeanpaper.pdf - Submitted Version - Requires a PDF viewer. Download (1524Kb) |
Official URL: http://dx.doi.org/10.1016/j.cmpb.2010.08.018
Abstract
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. | ||||
| ISSN: | 0169-2607 | ||||
| Official Date: | November 2011 | ||||
| Dates: |
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| Volume: | Vol.104 | ||||
| Number: | No.2 | ||||
| Page Range: | pp. 81-92 | ||||
| DOI: | 10.1016/j.cmpb.2010.08.018 | ||||
| Status: | Peer Reviewed | ||||
| Publication Status: | Published | ||||
| Access rights to Published version: | Restricted or Subscription Access |
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