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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

Analytical and Bioanalytical Chemistry volume 406, pages 1751–1762 (2014)Cite this article

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.

Conflict of interest

The authors declares no conflict of interest.

Author information

Author notes

  1. B. Forngren

    Present address: Cobra Biologics AB, 152 57, Södertälje, Sweden

  2. J. Lindberg

    Present address: Analytical Proof Sweden AB, 115 37, Stockholm, Sweden

  3. J. Öhd

    Present address: Shire AG, 1262, Eysins, Switzerland

Authors and Affiliations

  1. Department of Molecular Biology, Umeå University, 901 87, Umeå, Sweden

    J. Kolmert & A. Nordström

  2. Umeå Plant Science Center, Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences, 901 83, Umeå, Sweden

    J. Kolmert & T. Moritz

  3. Global Safety Assessment, AstraZeneca R&D, 151 85, Södertälje, Sweden

    J. Kolmert, B. Forngren & J. Lindberg

  4. Global Medicines Development, AstraZeneca R&D, 151 85, Södertälje, Sweden

    J. Öhd

  5. Department of Analytical Chemistry, Stockholm University, 106 91, Stockholm, Sweden

    J. Kolmert & K. M. Åberg

  6. Department of Medicine, Clinical Immunology and Allergy, Karolinska Institutet, 171 76, Stockholm, Sweden

    G. Nilsson

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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