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Capillary electrophoresis evidence for the stereoselective metabolism of itraconazole in man

journal contribution
posted on 2023-05-16, 18:58 authored by Michael BreadmoreMichael Breadmore, Thormann, W
Itraconazole (ITC) is a hydrophobic antimycotic drug with three chiral centers that is used clinically as a stereoisomeric mixture. A chiral capillary electrophoretic method for the separation of ITC stereoisomers and those of its main metabolite hydroxyitraconazole (HITC) was developed to determine the stereoselective nature of the ITC to HITC biotransformation. The method is based on the formation of inclusion complexes of the target analytes with the negatively charged sulfated -cyclodextrin in the presence of moderate concentrations of methanol in a low-pH phosphate buffer. The addition of polyethylene glycol 4000 was found to be critical in obtaining baseline resolution of eight peaks, two from ITC, four from HITC, and two from R051012 (internal standard), in under 20 min. Application of the developed procedure to serum samples from patients being treated with ITC showed clearly the presence of a stereoselective component in the metabolism of this antimycotic drug. This could be shown from in vitro incubations with single enzyme SupersomesTM to be in part due to the stereoselective formation of HITC by the human CYP3A4 enzyme. For one patient, monitoring of the ITC and HITC concentrations and peak ratios over a 103 day period of treatment with ITC showed a strong dependency of the chiral ITC ratio to the concentration of ITC, while the dominant enantiomeric ratio of HITC was largely independent of the total HITC concentration.

History

Publication title

Electrophoresis

Volume

24

Issue

15

Pagination

2588-2597

ISSN

0173-0835

Department/School

School of Natural Sciences

Publisher

Wiley

Place of publication

Weinheim

Rights statement

The definitive published version is available online at: http://interscience.wiley.com

Repository Status

  • Restricted

Socio-economic Objectives

Expanding knowledge in the chemical sciences

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