Optimized on-line enantioselective capillary electrophoretic method for kinetic and inhibition studies of drug metabolism mediated by cytochrome P450 enzymes.

Řemínek, Roman; Glatz, Zdeněk; Thormann, Wolfgang (2015). Optimized on-line enantioselective capillary electrophoretic method for kinetic and inhibition studies of drug metabolism mediated by cytochrome P450 enzymes. Electrophoresis, 36(11-12), pp. 1349-1357. Wiley-VCH 10.1002/elps.201400356

[img] Text
wt238-online Roman.pdf - Published Version
Restricted to registered users only
Available under License Publisher holds Copyright.

Download (515kB) | Request a copy

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 γ-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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute for Infectious Diseases > Laboratory for Clinical Pharmacology

UniBE Contributor:

Thormann, Wolfgang

ISSN:

0173-0835

Publisher:

Wiley-VCH

Language:

English

Submitter:

Wolfgang Thormann

Date Deposited:

02 May 2016 11:33

Last Modified:

02 May 2016 11:33

Publisher DOI:

10.1002/elps.201400356

PubMed ID:

25382218

Uncontrolled Keywords:

Capillary electrophoresis, Cytochrome P450 3A4, Dexmedetomidine, Enantioselective drug metabolism, Ketamine, Ketoconazole

BORIS DOI:

10.7892/boris.81574

URI:

https://boris.unibe.ch/id/eprint/81574

Actions (login required)

Edit item Edit item
Provide Feedback