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dc.date.accessioned2013-03-12T08:47:46Z
dc.date.issued2010en_US
dc.date.submitted2010-12-16en_US
dc.identifier.citationFinnøy, Anders Løvseth. Bias in Estimates of Metabolic Constants When Applying the Michaelis-Menten Equation to Drugs Exhibiting Atypical Enzyme Kinetics. Masteroppgave, University of Oslo, 2010en_US
dc.identifier.urihttp://hdl.handle.net/10852/11941
dc.description.abstractIt has been proposed that homotropic co-operativity in drug metabolism by CYP enzymes observed in vitro may have minimal impact on in vivo clearance at therapeutic drug concentrations [3]. Nevertheless, “force fitting” of in vitro data for substances that exhibit such behavior by a simple Michaelis-Menten function may introduce bias when predicting in vivo clearance. The aim of the present master thesis was to investigate the effect of ignoring atypical in vitro kinetics and using a simple Michaelis-Menten model to predict kinetic parameters. A two-site binding model (Scheme 5 and equation 6) and associated values of α (13.2) and β (0.41) taken from [4], together with a range of each of these values (0.01, 0.1, 1, 10, and 20) for 25 virtual compounds, were used to simulate rates of metabolism vs substrate concentration. The single point concentration data were then fitted with the Michaelis-Menten equation (Equation 17) using the proportional weighting option in the software GraFit Version 5. Intrinsic clearances (CLint) were calculated by dividing Vmax by Km, both values extracted from GraFit, and then compared to real intrinsic clearance that was calculated by dividing Vmax and Ks, both found in the literature [4]. In conclusion, the results in the thesis confirm that bias (0.01- to 100-fold) in estimates of CLint, Vmax and Km (Ks), and hence the prediction of drug clearance, can result if atypical in vitro enzyme kinetics are ignored and the data are fitted by simpler functions. In vitro kinetic parameters should therefore be estimated using the most appropriate model.nor
dc.description.abstractIt has been proposed that homotropic co-operativity in drug metabolism by CYP enzymes observed in vitro may have minimal impact on in vivo clearance at therapeutic drug concentrations [3]. Nevertheless, “force fitting” of in vitro data for substances that exhibit such behavior by a simple Michaelis-Menten function may introduce bias when predicting in vivo clearance. The aim of the present master thesis was to investigate the effect of ignoring atypical in vitro kinetics and using a simple Michaelis-Menten model to predict kinetic parameters. A two-site binding model (Scheme 5 and equation 6) and associated values of α (13.2) and β (0.41) taken from [4], together with a range of each of these values (0.01, 0.1, 1, 10, and 20) for 25 virtual compounds, were used to simulate rates of metabolism vs substrate concentration. The single point concentration data were then fitted with the Michaelis-Menten equation (Equation 17) using the proportional weighting option in the software GraFit Version 5. Intrinsic clearances (CLint) were calculated by dividing Vmax by Km, both values extracted from GraFit, and then compared to real intrinsic clearance that was calculated by dividing Vmax and Ks, both found in the literature [4]. In conclusion, the results in the thesis confirm that bias (0.01- to 100-fold) in estimates of CLint, Vmax and Km (Ks), and hence the prediction of drug clearance, can result if atypical in vitro enzyme kinetics are ignored and the data are fitted by simpler functions. In vitro kinetic parameters should therefore be estimated using the most appropriate model.eng
dc.language.isonoben_US
dc.titleBias in Estimates of Metabolic Constants When Applying the Michaelis-Menten Equation to Drugs Exhibiting Atypical Enzyme Kineticsen_US
dc.typeMaster thesisen_US
dc.date.updated2011-11-29en_US
dc.creator.authorFinnøy, Anders Løvsethen_US
dc.date.embargoenddate10000-01-01
dc.rights.termsDette dokumentet er ikke elektronisk tilgjengelig etter ønske fra forfatter. Tilgangskode/Access code Aen_US
dc.rights.termsforeveren_US
dc.subject.nsiVDP::568en_US
dc.identifier.bibliographiccitationinfo:ofi/fmt:kev:mtx:ctx&ctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&rft.au=Finnøy, Anders Løvseth&rft.title=Bias in Estimates of Metabolic Constants When Applying the Michaelis-Menten Equation to Drugs Exhibiting Atypical Enzyme Kinetics&rft.inst=University of Oslo&rft.date=2010&rft.degree=Masteroppgaveen_US
dc.identifier.urnURN:NBN:no-28389en_US
dc.type.documentMasteroppgaveen_US
dc.identifier.duo110035en_US
dc.contributor.supervisorHege Christensenen_US
dc.identifier.bibsys114895619en_US
dc.rights.accessrightsclosedaccessen_US
dc.identifier.fulltextFulltext https://www.duo.uio.no/bitstream/handle/10852/11941/2/Masteroppgave_Anders_Finnoy.pdf


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