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http://dx.doi.org/10.18419/opus-1908
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DC Element | Wert | Sprache |
---|---|---|
dc.contributor.author | Bucher, Joachim | de |
dc.contributor.author | Riedmaier, Stephan | de |
dc.contributor.author | Schnabel, Anke | de |
dc.contributor.author | Marcus, Katrin | de |
dc.contributor.author | Vacun, Gabriele | de |
dc.contributor.author | Weiss, Thomas S. | de |
dc.contributor.author | Thasler, Wolfgang E. | de |
dc.contributor.author | Nüssler, Andreas K. | de |
dc.contributor.author | Zanger, Ulrich M. | de |
dc.contributor.author | Reuss, Matthias | de |
dc.date.accessioned | 2011-07-28 | de |
dc.date.accessioned | 2016-03-31T07:52:54Z | - |
dc.date.available | 2011-07-28 | de |
dc.date.available | 2016-03-31T07:52:54Z | - |
dc.date.issued | 2011 | de |
dc.identifier.other | 34795605X | de |
dc.identifier.uri | http://nbn-resolving.de/urn:nbn:de:bsz:93-opus-63606 | de |
dc.identifier.uri | http://elib.uni-stuttgart.de/handle/11682/1925 | - |
dc.identifier.uri | http://dx.doi.org/10.18419/opus-1908 | - |
dc.description.abstract | Background The individual character of pharmacokinetics is of great importance in the risk assessment of new drug leads in pharmacological research. Amongst others, it is severely influenced by the properties and inter-individual variability of the enzymes and transporters of the drug detoxification system of the liver. Predicting individual drug biotransformation capacity requires quantitative and detailed models. Results In this contribution we present the de novo deterministic modeling of atorvastatin biotransformation based on comprehensive published knowledge on involved metabolic and transport pathways as well as physicochemical properties. The model was evaluated on primary human hepatocytes and parameter identifiability analysis was performed under multiple experimental constraints. Dynamic simulations of atorvastatin biotransformation considering the inter-individual variability of the two major involved enzymes CYP3A4 and UGT1A3 based on quantitative protein expression data in a large human liver bank (n = 150) highlighted the variability in the individual biotransformation profiles and therefore also points to the individuality of pharmacokinetics. Conclusions A dynamic model for the biotransformation of atorvastatin has been developed using quantitative metabolite measurements in primary human hepatocytes. The model comprises kinetics for transport processes and metabolic enzymes as well as population liver expression data allowing us to assess the impact of inter-individual variability of concentrations of key proteins. Application of computational tools for parameter sensitivity analysis enabled us to considerably improve the validity of the model and to create a consistent framework for precise computer-aided simulations in toxicology. | en |
dc.language.iso | en | de |
dc.rights | info:eu-repo/semantics/openAccess | de |
dc.subject.classification | Systembiologie , Dynamische Modellierung , Pharmakokinetik , Statine | de |
dc.subject.ddc | 570 | de |
dc.subject.other | Inter-individuelle Variabilität , humane Hepatozyten | de |
dc.subject.other | Systems Biology , Dynamic Modeling , Pharmacokinetics , Statins , Human Hepatocytes | en |
dc.title | A systems biology approach to dynamic modeling and inter-subject variability of statin pharmacokinetics in human hepatocytes | en |
dc.type | article | de |
dc.date.updated | 2011-07-28 | de |
ubs.bemerkung.extern | Vollständige Lizenzbedingungen siehe: <a href="http://www.biomedcentral.com/info/authors/license">http://www.biomedcentral.com/info/authors/license</a> | de |
ubs.fakultaet | Fakultät Energie-, Verfahrens- und Biotechnik | de |
ubs.fakultaet | Fakultätsübergreifend / Sonstige Einrichtung | de |
ubs.fakultaet | Externe wissenschaftliche Einrichtungen | de |
ubs.institut | Institut für Bioverfahrenstechnik | de |
ubs.institut | Sonstige Einrichtung | de |
ubs.institut | Fraunhofer-Institut für Grenzflächen- und Bioverfahrenstechnik (IGB) | de |
ubs.opusid | 6360 | de |
ubs.publikation.source | BMC Systems Biology 5 (2011), Nr. 66. URL http://dx.doi.org./10.1186/1752-0509-5-66 | de |
ubs.publikation.typ | Zeitschriftenartikel | de |
Enthalten in den Sammlungen: | 04 Fakultät Energie-, Verfahrens- und Biotechnik |
Dateien zu dieser Ressource:
Datei | Beschreibung | Größe | Format | |
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1752_0509_5_66.pdf | Full text | 654,86 kB | Adobe PDF | Öffnen/Anzeigen |
Additional_file_1.pdf | Additional file 1 | 28,15 kB | Adobe PDF | Öffnen/Anzeigen |
Additional_file_2.pdf | Additional file 2 | 18,36 kB | Adobe PDF | Öffnen/Anzeigen |
Additional_file_3.pdf | Additional file 3 | 11,66 kB | Adobe PDF | Öffnen/Anzeigen |
Additional_file_4.pdf | Additional file 4 | 178,79 kB | Adobe PDF | Öffnen/Anzeigen |
Additional_file_5.pdf | Additional file 5 | 9,46 kB | Adobe PDF | Öffnen/Anzeigen |
Additional_file_6.pdf | Additional file 6 | 9,63 kB | Adobe PDF | Öffnen/Anzeigen |
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