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Capillary electrophoresis evidence for the stereoselective metabolism of itraconazole in man


Breadmore, MC and Thormann, W, Capillary electrophoresis evidence for the stereoselective metabolism of itraconazole in man, Electrophoresis, 24, (15) pp. 2588-2597. ISSN 0173-0835 (2003) [Refereed Article]

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DOI: doi:10.1002/elps.200305494


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.

Item Details

Item Type:Refereed Article
Keywords:Chiral capillary electrophoresis Hydroxyitraconazole Itraconazole Plasma Serum Sulfated -cyclodextrin
Research Division:Chemical Sciences
Research Group:Analytical chemistry
Research Field:Separation science
Objective Division:Expanding Knowledge
Objective Group:Expanding knowledge
Objective Field:Expanding knowledge in the chemical sciences
UTAS Author:Breadmore, MC (Professor Michael Breadmore)
ID Code:43544
Year Published:2003
Web of Science® Times Cited:29
Deposited By:Chemistry
Deposited On:2007-03-15
Last Modified:2010-03-16

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