Generic Method for Cytochrome P450 Metabolism Studies Employing Short End Injection Capillary Electrophoresis Mode

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Authors

ŘEMÍNEK Roman SEDLÁČKOVÁ Jana PAKOSTOVÁ Eva MÁDR Aleš GLATZ Zdeněk

Year of publication 2011
Type Conference abstract
MU Faculty or unit

Faculty of Science

Citation
Description Cytochromes P450 (CYP) play a key role in metabolism of more than 60 % currently prescribed drugs [1], therefore stability against this group of enzymes represents one of the important drug parameters. Pharmaceutical companies strive to determine the action of CYP on a new drug candidate early within development process in order to eliminate compounds with inappropriate qualities and thus economize following tests. Human liver microsomes (HLM) constitute a favourable screening media for this purpose offering fast analyses, high CYP concentration and good simulation of metabolism inside the liver tissue. The aim of this study was to introduce a method based on capillary electrophoresis (CE) allowing both assessment of drug stability against HLM and determination of main CYP isoform responsible for a metabolism of a given drug. The method based on NADP+ production monitoring was employed to ensure its generic character enabling screening of large groups of miscellaneous compounds. Conceptually, particular CYP isoform responsible for metabolism of a new drug candidate is then determined by decrease in NADP+ production in reaction with its specific inhibitor. Finally, the generic method enabling fast assessment of relation between a new drug candidate and CYP in human liver was established. Separation of reaction mixture components was achieved within 2 minutes analysis with 20 mM phosphate-borate buffer pH 8.6 primarily due to combination of CE short end injection mode and application of high voltage of -30 kV. Presented method thus represents a promising tool for high-throughput screenings of candidate compounds within early stages of a new drug development.
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