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Semi-physiologically based pharmacokinetic modeling of paclitaxel metabolism and in silico-based study of the dynamic sensitivities in pathway kinetics
KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
2012 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 47, no 4, 759-767 p.Article in journal (Refereed) Published
Abstract [en]

Purpose: To build a semi-physiologically based pharmacokinetic model describing the uptake, metabolism and efflux of paclitaxel and its metabolites and investigate the effect of hypothetical genetic polymorphisms causing reduced uptake, metabolism or efflux in the pathway by model simulation and sensitivity analysis. Methods: A previously described intracellular pharmacokinetic model was used as a starting point for model development. Kinetics for metabolism, transport, binding and systemic and output compartments were added to mimic a physiological model with hepatic elimination. Model parameters were calibrated using constraints postulated as ratios of concentrations and amounts of metabolites and drug in the systemic plasma and output compartments. The sensitivity in kinetic parameters was tested using dynamic sensitivity analysis. Results: Predicted plasma concentrations of drug and metabolites were in the range of what has been observed in clinical studies. Given the final model, plasma concentrations of paclitaxel seems to be relatively little affected by changes in metabolism or transport, while its main metabolite may be largely affected even by small changes. If metabolites prove to be clinically relevant, genetic polymorphisms may play an important role for individualizing paclitaxel treatment.

Place, publisher, year, edition, pages
2012. Vol. 47, no 4, 759-767 p.
Keyword [en]
Paclitaxel metabolism, Mathematical modeling, Pharmacokinetics, Sensitivity analysis, CYP2C8, CYP3A4
National Category
Social and Clinical Pharmacy
URN: urn:nbn:se:kth:diva-109187DOI: 10.1016/j.ejps.2012.08.002ISI: 000311464900015ScopusID: 2-s2.0-84866479269OAI: diva2:582916
Swedish Research CouncilScience for Life Laboratory - a national resource center for high-throughput molecular bioscience

QC 20130107

Available from: 2013-01-07 Created: 2012-12-21 Last updated: 2013-01-07Bibliographically approved

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Gréen, Henrik
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Gene TechnologyScience for Life Laboratory, SciLifeLab
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