Development of a highly sensitive liquid chromatography–mass spectrometry method to quantify plasma leukotriene E4 and demonstrate pharmacological suppression of endogenous 5-LO pathway activity in man

•A robust ultra-sensitive SPE-UPLC-MS/MS method for LTE4 in human plasma was successfully developed•For the first time we demonstrated that pharmacological inhibition of 5-LO pathway activity can suppress basal endogenous levels of LTE4 in plasma•The ability to quantify plasma LTE4 provides an alter...

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Published in:Prostaglandins & other lipid mediators 2020-10, Vol.150, p.106463-106463, Article 106463
Main Authors: Löfgren, Lars, Forsberg, Gun-Britt, Davidsson, Pia, Eketjäll, Susanna, Whatling, Carl
Format: Article
Language:English
Subjects:
5-lipoxygenase
AZD5718
Cardiovascular disease
FLAP
Leukotriene E4
Liquid chromatography
LTE4
Mass spectrometry
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cited_by cdi_FETCH-LOGICAL-c278t-d604d9c77a5c8ca535651efaac7d33500e08297f4bd2c9a66bff5b33f07acfe03
cites cdi_FETCH-LOGICAL-c278t-d604d9c77a5c8ca535651efaac7d33500e08297f4bd2c9a66bff5b33f07acfe03
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container_title Prostaglandins & other lipid mediators
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creator Löfgren, Lars
Forsberg, Gun-Britt
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description •A robust ultra-sensitive SPE-UPLC-MS/MS method for LTE4 in human plasma was successfully developed•For the first time we demonstrated that pharmacological inhibition of 5-LO pathway activity can suppress basal endogenous levels of LTE4 in plasma•The ability to quantify plasma LTE4 provides an alternative biomarker to urine LTE4 to assess endogenous 5-LO pathway activity in man. Low basal endogenous concentrations (
doi_str_mv 10.1016/j.prostaglandins.2020.106463
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Low basal endogenous concentrations (&lt;20 pg/mL) of the 5-lipoxygenase (5-LO) pathway biomarker leukotriene E4 (LTE4) in human plasma present a significant analytical challenge. Analytical methods including liquid chromatography–mass spectrometry and enzyme linked immunosorbent assays have been used to quantify plasma LTE4 in the past but have not provided consistent data in the lower pg/mL-range. With our new method, a detection limit (&lt;1 pg/mL plasma) significantly below basal levels of LTE4 was achieved by combining large volume sample purification and enrichment by anion-exchange mixed mode solid phase extraction (SPE) with large volume injection followed by chromatographic separation by ultra performance liquid chromatography (UPLC) and quantification by highly sensitive negative-ion electrospray tandem mass spectrometry (MS/MS). The method was reproducible, accurate and linear between 1 and 120 pg/mL plasma LTE4. The method was used to perform an analysis of plasma samples collected from healthy volunteers in a Phase 1 study with the FLAP (5-lipoxygenase activating protein) inhibitor AZD5718. Basal endogenous LTE4 levels of 5.1 ± 2.7 pg/mL were observed in healthy volunteers (n = 34). 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Low basal endogenous concentrations (&lt;20 pg/mL) of the 5-lipoxygenase (5-LO) pathway biomarker leukotriene E4 (LTE4) in human plasma present a significant analytical challenge. Analytical methods including liquid chromatography–mass spectrometry and enzyme linked immunosorbent assays have been used to quantify plasma LTE4 in the past but have not provided consistent data in the lower pg/mL-range. With our new method, a detection limit (&lt;1 pg/mL plasma) significantly below basal levels of LTE4 was achieved by combining large volume sample purification and enrichment by anion-exchange mixed mode solid phase extraction (SPE) with large volume injection followed by chromatographic separation by ultra performance liquid chromatography (UPLC) and quantification by highly sensitive negative-ion electrospray tandem mass spectrometry (MS/MS). The method was reproducible, accurate and linear between 1 and 120 pg/mL plasma LTE4. 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Low basal endogenous concentrations (&lt;20 pg/mL) of the 5-lipoxygenase (5-LO) pathway biomarker leukotriene E4 (LTE4) in human plasma present a significant analytical challenge. Analytical methods including liquid chromatography–mass spectrometry and enzyme linked immunosorbent assays have been used to quantify plasma LTE4 in the past but have not provided consistent data in the lower pg/mL-range. With our new method, a detection limit (&lt;1 pg/mL plasma) significantly below basal levels of LTE4 was achieved by combining large volume sample purification and enrichment by anion-exchange mixed mode solid phase extraction (SPE) with large volume injection followed by chromatographic separation by ultra performance liquid chromatography (UPLC) and quantification by highly sensitive negative-ion electrospray tandem mass spectrometry (MS/MS). The method was reproducible, accurate and linear between 1 and 120 pg/mL plasma LTE4. 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source ScienceDirect Freedom Collection 2022-2024
subjects 5-lipoxygenase
AZD5718
Cardiovascular disease
FLAP
Leukotriene E4
Liquid chromatography
LTE4
Mass spectrometry
title Development of a highly sensitive liquid chromatography–mass spectrometry method to quantify plasma leukotriene E4 and demonstrate pharmacological suppression of endogenous 5-LO pathway activity in man
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