p450 - publications

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1. J Chromatogr A. 2012 Mar 7. [Epub ahead of print]

Simultaneous determination of fluoxetine and norfluoxetine enantiomers using
isotope discrimination mass spectroscopy solution method and its application in
the CYP2C9-mediated stereoselective interactions.

Yu L, Wang S, Jiang H, Zhou H, Zeng S.

College of Pharmaceutical Sciences, Zhejiang University, 886 Yuhangtang Road,
Hangzhou, Zhejiang 310058, China.

In this study, we developed an LC-MS/MS method based on an isotope discrimination
mass spectroscopy solution (IDMSS) technology to simultaneously quantify
enantiomers of fluoxetine (FLX) and norfluoxetine (NFLX) in a CYP2C9 incubation
mixture. S-FLX and S-NFLX were labeled to form S-FLX-d5 and S-NFLX-d5. The method
has several advantages over conventional chiral separation methods, in terms of
the analysis period, resolution, and lower limit of quantification. The primary
advantage of the method is that the two enantiomers can always be simultaneously
determined by mass spectroscopy regardless if they are separated on column or
not, owing to which it has high throughput and high sensitivity. The lower limit
of quantification (amount on column) is 12.5 and 1.25pg for FLX and NFLX,
respectively. The retention time of FLX, NFLX, and the internal standard is only
1.9min. The calibration curves were linear over the concentration range of
0.1-100ng/ml for NFLX and 1-1000ng/ml for FLX with an accepted reproducible
(RSD<10%) and accurate (CV<10%). No significant kinetic isotope effect was found
in the metabolism of S-FLX-d5 catalyzed by CYP2C9*1 and CYP2C9*2. The
half-maximal inhibitory concentration values between R-FLX and S-FLX catalyzed by
CYP2C9*1 and CYP2C9*2 were determined in this study. The inhibitory effects of R-
to S-FLX were stronger than those of S- to R-FLX in both CYP2C9*1 and CYP2C9*2.
The IDMSS technology is useful for stereoselective study of chiral compound in

Copyright © 2012 Elsevier B.V. All rights reserved.

PMID: 22436668 [PubMed - as supplied by publisher]