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A quantitative LC/MS method targeting urinary 1-methyl-4-imidazoleacetic acid for safety monitoring of the global histamine turnover in clinical studies

Abstract

Anaphylaxis is a potentially life-threatening condition triggered mainly by the release of inflammatory mediators, notably histamine. In pharmaceutical research, drug discovery, and clinical evaluation, it may be necessary to accurately assess the potential of a compound, event, or disorder to promote the release of histamine. In contrast to the measurement of plasma histamine, determination of the stable metabolite 1-methyl-4-imidazoleacetic acid (tele-MIAA) in urine provides a noninvasive and more reliable methodology to monitor histamine release. This study presents a repeatable high-performance liquid chromatography coupled to electrospray mass spectrometry (LC–ESI–MS) method where tele-MIAA is baseline separated from its structural isomer 1-methyl-5-imidazoleacetic acid (pi-MIAA) and an unknown in human urine. The ion-pairing chromatography method, in reversed-phase mode, based on 0.5 mM tridecafluoroheptanoic acid demonstrated high repeatability and was applied in a clinical development program that comprised a large number of clinical samples from different cohorts. The inter- and intra-run precision of the method for tele-MIAA were 8.4 and 4.3 %, respectively, at the mean urinary concentration level, while method accuracy was between −16.2 and 8.0 % across the linear concentration range of 22–1,111 ng mL−1. Overall, method precision was greater than that reported in previously published methods and enabled the identification of gender differences that were independent of age or demography. The median concentration measured in female subjects was 3.0 μmol mmol−1 of creatinine, and for male subjects, it was 2.1 μmol mmol−1 of creatinine. The results demonstrate that the method provides unprecedented accuracy, precision, and practicality for the measurement of tele-MIAA in large clinical settings.

Assessment of global histamine turnover by means of urinary tele-MIAA determination

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Acknowledgments

Authors J. Kolmert, B. Forngren, J. Lindberg, and J. Öhd were all full-time employees at AstraZeneca R&D Södertälje during the time of study design, conduct, experimental analysis, and part of the writing period. The authors thank Göran Granerus for the kind supply of reference compound (tele-MIAA). Senior statistician Gunnar Nordahl is acknowledged for his clinical statistical advice and Anita Lundblad and Helena Hallberg for experimental help—all former employees at AstraZeneca R&D Sodertalje Sweden. We also thank Gunnar Thorsén Department of Analytical Chemistry, Stockholm University for constructive discussions regarding peak splitting. Financial support of the Jane and Dan Olsson Foundations (AN) is gratefully acknowledged.

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The authors declares no conflict of interest.

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Kolmert, J., Forngren, B., Lindberg, J. et al. A quantitative LC/MS method targeting urinary 1-methyl-4-imidazoleacetic acid for safety monitoring of the global histamine turnover in clinical studies. Anal Bioanal Chem 406, 1751–1762 (2014). https://doi.org/10.1007/s00216-013-7594-6

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  • DOI: https://doi.org/10.1007/s00216-013-7594-6

Keywords

  • tele-MIAA
  • HILIC
  • Ion-pairing chromatography
  • Ion suppression
  • LC/MS
  • Clinical biomarker