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

• Published in: Journal of pharmaceutical analysis Vol. 10; no. 2; pp. 157 - 163
• Main Authors: Gyamfi, Obed A., Bortey-Sam, Nesta, Donkor, Abigail B., White, Carl W., Logue, Brian A.
• Format: Journal Article
• Language: English
• Published: China Elsevier B.V 01.04.2020; Xi'an Jiaotong University, Journal of Pharmaceutical Analysis; Department of Chemistry and Biochemistry,South Dakota State University,Box 2202,Brookings,SD,57007,USA%Pediatrics-Pulmonary Medicine,University of Colorado-Denver,Denver,CO,80045,USA; Xi'an Jiaotong University; Elsevier
• Subjects: Ankyrins; Antagonists; Bioavailability; Chlorine; Chromatography; High-performance liquid chromatography; HPLC-MS/MS; Inhalation; Isocyanates; Laboratory animals; Method development; Neurons; Original; Pain; Pharmacokinetics; Plasma; Scientific imaging; Storage conditions; Toxic inhalation hazard (TIH); Transient receptor potential (TRP) ion channel; Transient receptor potential proteins; United States > US; Toxic inhalation hazard (TIH); HPLC-MS/MS; Transient receptor potential (TRP) ion channel; Method development; Pharmacokinetics
• ISSN: 2095-1779; 2214-0883
• DOI: 10.1016/j.jpha.2019.12.005

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. [Display omitted] •A-967079 is a TRPA1 antagonist and a promising toxic inhalation hazard antidote.•The method presented is the first fully validated method for analysis A-967079 of from any matrix.•The method includes simple sample preparation and analysis from plasma.•The method can detect 25 nM (LOD) and features wide linear range (0.05–200 μM) of A-967079 in plasma.•Preliminary pharmacokinetic behavior of A-967079 was demonstrated in rats.