Enantioselective capillary electrophoresis for the assessment of CYP3A4-mediated ketamine demethylation and inhibition in vitro

Kwan, Hiu Ying; Thormann, Wolfgang (2011). Enantioselective capillary electrophoresis for the assessment of CYP3A4-mediated ketamine demethylation and inhibition in vitro. Electrophoresis, 32(19), pp. 2738-45. Weinheim: Wiley-VCH 10.1002/elps.201100095

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Enantioselective CE with sulfated cyclodextrins as chiral selectors was used to determine the CYP3A4-catalyzed N-demethylation kinetics of ketamine to norketamine and its inhibition in the presence of ketoconazole in vitro. Ketamine, a chiral phencyclidine derivative, was incubated with recombinant human CYP3A4 from a baculovirus expression system as racemic mixture and as single enantiomer. Alkaline liquid/liquid extracts of the samples were analyzed with a pH 2.5 buffer comprising 50 mM Tris and phosphoric acid together with either multiple isomer sulfated β-cyclodextrin (10 mg/mL) or highly sulfated γ-cyclodextrin (2%, w/v). Data obtained in the absence of ketoconazole revealed that the N-demethylation occurred stereoselectively with Michaelis-Menten (incubation of racemic ketamine) and Hill (separate incubation of single enantiomers) kinetics. Data generated in the presence of ketoconazole as the inhibitor could best be fitted to a one-site competitive model and inhibition constants were calculated using the equation of Cheng and Prusoff. No stereoselective difference was observed, but inhibition constants for the incubation of racemic ketamine were found to be larger compared with those obtained with the incubation of single ketamine enantiomers.

Item Type:

Journal Article (Original Article)

Division/Institute:

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

UniBE Contributor:

Kwan, Hiu and Thormann, Wolfgang

ISSN:

0173-0835

Publisher:

Wiley-VCH

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:25

Last Modified:

06 Dec 2013 13:30

Publisher DOI:

10.1002/elps.201100095

PubMed ID:

21983822

Web of Science ID:

000296606000017

URI:

https://boris.unibe.ch/id/eprint/8909 (FactScience: 214561)

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