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. 2020 Apr;10(2):157-163.
doi: 10.1016/j.jpha.2019.12.005. Epub 2019 Dec 13.

Analysis of TRPA1 antagonist, A-967079, in plasma using high-performance liquid chromatography tandem mass-spectrometry

Obed A Gyamfi  1 , Nesta Bortey-Sam  1 , Abigail B Donkor  1 , Carl W White  2 , Brian A Logue  1
Affiliations

Analysis of TRPA1 antagonist, A-967079, in plasma using high-performance liquid chromatography tandem mass-spectrometry

Obed A Gyamfi et al. J Pharm Anal. 2020 Apr.

Abstract

The noxious effects from exposure to toxic inhalation hazards (TIHs, such as isocyanates, chlorine, etc.) are known to be triggered by the activation of transient receptor potential ankyrin 1 (TRPA1) ion channel. Antagonists of TRPA1 have shown near complete attenuation of the noxious effects from TIH exposure. One of the TRPA1 antagonists, (1E,3E)-1-(4-fluorophenyl)-2-methyl-1-pentene-3-one oxime (A-967079), has shown impressive efficacy, high selectivity, high potency, and oral bioavailability. Although a validated method to quantify A-967079 in biological matrices is vital for the further development of A-967079 as a therapeutic agent, no method for its analysis from any matrix is currently available. Hence, a rapid and simple HPLC-MS/MS method was developed and validated to quantify A-967079 in rabbit plasma. The method presented here features an excellent LOD of 25 nM and a wide linear range (0.05-200 μM), with good accuracy and precision (100 ± 10.5% and <14.2% relative standard deviation, respectively). The stability of A-967079 in plasma was excellent for most of the storage conditions evaluated. The method was successfully applied to determine A-967079 from treated animals and it may facilitate the development of this TRPA1 antagonist as a therapeutic agent against the noxious effects of TIH exposure.

Keywords: HPLC-MS/MS; Method development; Pharmacokinetics; Toxic inhalation hazard (TIH); Transient receptor potential (TRP) ion channel.

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Figures

Image 1
Graphical abstract
Fig. 1
Fig. 1
Chemical structures of TRPA1 antagonists with their respective identification.
Fig. 2
Fig. 2
Representative ESI(+) mass spectra of A-967079 and identification of the abundant ions. A-967079 (207 Da) undergoes Beckmann rearrangement to produce a 209 Da product.
Fig. 3
Fig. 3
Representative HPLC-MS/MS chromatograms of spiked (5 μM) and non-spiked A-967079 in rabbit plasma. The chromatograms represent signal response to the MRM transitions of A-967079 (209 → 191 and 209 → 162 m/z).
Fig. 4
Fig. 4
HPLC-MS/MS chromatogram from the plasma of A-967079-treated rats and rat plasma obtained prior to A-967079 treatment. The chromatograms represent signal response to MRM quantification transition of A-967079 (209 → 162 m/z).
Fig. 5
Fig. 5
Plasma concentration-time pharmacokinetic profile of A-967079 following intravenous administration of A-967079 to rats. Error bars represent standard error of the mean (SEM, n = 3). Inset: Representation of elimination constant (Kel) of A-967079 by log concentration-time graph.
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