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@article{1213623,
author = {Řemínek, Roman and Glatz, Zdeněk and Thormann, Wolfgang},
article_location = {Weinheim},
article_number = {11-12},
doi = {http://dx.doi.org/10.1002/elps.201400356},
keywords = {CE; Cytochrome P450; Drug Metabolism;},
language = {eng},
issn = {0173-0835},
journal = {Electrophoresis},
title = {Optimized On-Line Enantioselective Capillary Electrophoretic Method for Kinetic and Inhibition Studies of Drug Metabolism Mediated by Cytochrome P450 Enzymes},
volume = {36},
year = {2015}
}
TY - JOUR
ID - 1213623
AU - Řemínek, Roman - Glatz, Zdeněk - Thormann, Wolfgang
PY - 2015
TI - Optimized On-Line Enantioselective Capillary Electrophoretic Method for Kinetic and Inhibition Studies of Drug Metabolism Mediated by Cytochrome P450 Enzymes
JF - Electrophoresis
VL - 36
IS - 11-12
SP - 1349-1357
EP - 1349-1357
PB - WILEY-VCH Verlag GmbH
SN - 01730835
KW - CE
KW - Cytochrome P450
KW - Drug Metabolism;
N2 - Pharmacokinetic and pharmacodynamic properties of a chiral drug can significantly differ between application of the racemate and single enantiomers. During drug development, the characteristics of candidate compounds have to be assessed prior to clinical testing. Since biotransformation significantly influences drug actions in an organism, metabolism studies represent a crucial part of such tests. Hence, an optimized and economical capillary electrophoretic method for on-line studies of the enantioselective drug metabolism mediated by cytochrome P450 enzymes was developed. It comprises a diffusion-based procedure, which enables mixing of the enzyme with virtually any compound inside the nanoliter-scale capillary reactor and without the need of additional optimization of mixing conditions. For CYP3A4, ketamine as probe substrate and highly sulfated gama-cyclodextrin as chiral selector, improved separation conditions for ketamine and norketamine enantiomers compared to a previously published electrophoretically mediated microanalysis method were elucidated. The new approach was thoroughly validated for the CYP3A4 mediated N-demethylation pathway of ketamine and applied to the determination of its kinetic parameters and the inhibition characteristics in presence of ketoconazole and dexmedetomidine. The determined parameters were found to be comparable to literature data obtained with different techniques. The presented method constitutes a miniaturized and cost-effective tool which should be suitable for the assessment of the stereoselective aspects of kinetic and inhibition studies of cytochrome P450-mediated metabolic steps within early stages of the development of a new drug.
ER -
ŘEMÍNEK, Roman, Zdeněk GLATZ and Wolfgang THORMANN. Optimized On-Line Enantioselective Capillary Electrophoretic Method for Kinetic and Inhibition Studies of Drug Metabolism Mediated by Cytochrome P450 Enzymes. \textit{Electrophoresis}. Weinheim: WILEY-VCH Verlag GmbH, 2015, vol.~36, 11-12, p.~1349-1357. ISSN~0173-0835. Available from: https://dx.doi.org/10.1002/elps.201400356.
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