Analysis of trans-2,6-difluoro-4′-(N,N-dimethylamino)stilbene (DFS) in biological samples by liquid chromatography-tandem mass spectrometry: metabolite identification and pharmacokinetics

Samuel Chao Ming Yeo, Vitaliy M. Sviripa, Meng Huang, Liliia Kril, David S. Watt, Chunming Liu, Hai Shu Lin

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15 Scopus citations

Abstract

The metabolism of a promising antineoplastic agent, trans-2,6-difluoro-4′-(N,N-dimethylamino)stilbene (DFS), was studied in mouse, rat, and human liver microsomes using liquid chromatography-tandem mass spectrometry (LC-MS/MS) with the multiple reaction monitoring-information-dependent acquisition-enhanced product ion scan (MRM-IDA-EPI) method. Ten putative metabolites were identified and the structures of four metabolites were confirmed using authentic standards. Since trans-2,6-difluoro-4′-(N-methylamino)stilbene (DMDFS, M1) was present in all species as metabolite and displayed in vitro growth inhibition superior to DFS, its pharmacokinetic profiles were examined in Sprague–Dawley rats using DFS as a comparator. A reliable LC-MS/MS multiple reaction monitoring (MRM) method was subsequently developed and validated for the simultaneous quantification of both DFS and DMDFS in rat plasma for this purpose. Upon intravenous administration (4 mg/kg), DFS had a moderate clearance (Cl = 62.7 ± 23.2 mL/min/kg), terminal elimination half-life (t1/2 λZ = 299 ± 73 min), and mean transit time (MTT = 123 ± 14 min) with demethylation metabolism accounting for about 10 % of its total clearance. DMDFS possessed an intravenous pharmacokinetic profile similar to DFS. During oral dosing (10 mg/kg) where both DFS and DMDFS were absorbed rapidly, the oral bioavailability of DFS was approximately 2-fold greater than that of DMDFS (DFS: F = 42.1 ± 12.8 %; DMDFS: F = 18.7 ± 3.9 %). Interestingly, the DMDFS exposure after oral dosing of DFS (10 mg/kg) was comparable to that after oral administration of DMDFS (10 mg/kg) alone. As DFS displayed potent anticancer activities and excellent pharmacokinetic profiles, it appears to be a favorable candidate for further pharmaceutical development.

Original languageEnglish
JournalAnalytical and Bioanalytical Chemistry
Volume407
Issue number24
DOIs
StateAccepted/In press - Jul 31 2015

Bibliographical note

Publisher Copyright:
© 2015 Springer-Verlag Berlin Heidelberg

Keywords

  • Liquid chromatography-tandem mass spectrometry
  • Metabolite identification
  • Pharmacokinetics
  • trans-2,6-Difluoro-4′-(N,N-dimethylamino)stilbene
  • trans-2,6-Difluoro-4′-(N-methylamino)stilbene

ASJC Scopus subject areas

  • Analytical Chemistry
  • Biochemistry

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