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 ...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 vali-dated 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(0.05-200μM),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.展开更多
基金support from the CounterACT ProgramNational Institutes of Health Office of the Directorthe National Institute of Environmental Health Sciences(NIEHS),Grant number U54ES027698(CWW)。
文摘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 vali-dated 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(0.05-200μM),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.
