Perspectives of Quantitative GC-MS, LC-MS, and ICP-MS in the Clinical Medicine Science-The Role of Analytical Chemistry

Abstract

Mass spectrometry (MS) is the only instrumental analytical technology that utilizes unique properties of matter, that is, its mass (m) and electrical charge (z). In the magnetic and/or electric fields of mass spectrometers, electrically charged native or chemically modified (millions) endogenous and (thousands) exogenous substances, the analytes, are separated according to their characteristic mass-to-charge ratio (m/z) values. Mass spectrometers coupled to gas chromatographs (GC) or liquid chromatographs (LC), the so-called hyphenated techniques, i.e., GC-MS and LC-MS, respectively, enable reliable determination of the concentration of analytes in complex biological samples such as plasma, serum, and urine. A particular technology is represented by inductively coupled plasma-mass spectrometry (ICP-MS), which is mainly used for the analysis of metal ions. The highest analytical accuracy is reached by using mass spectrometers with high mass resolution (HR) or by tandem mass spectrometers, as it can be realized with quadrupole-type instruments, such as GC-MS/MS and LC-MS/MS, in combination with stable-isotope labeled analytes that serve as internal standards, like a standard weight in scales. GC-MS belongs to the oldest and most advanced instrumental analytical technology. From the very beginning, GC-MS found broad application in basic and applied research sciences. GC-MS has played important roles in discovering biochemical pathways, exploring underlying mechanisms of disease, and establishing new evidence-based pharmacological therapy. In this article, we make an inventory of the use of instrumental mass spectrometry in the life sciences and attempt to provide a perspective study on the future of analytical mass spectrometry in clinical science, mainly focusing on GC-MS and LC-MS. We used information freely available in the scientific database PubMed (retrieved in August-November 2024). Specific search terms such as GC-MS (103,000 articles), LC-MS (113,000 articles), and ICP-MS (14,000 articles) were used in the Title/Abstract in the "PubMed Advanced Search Builder" including filters such as search period (1970-2024). In total, around 103,000 articles on GC-MS, 113,000 articles on LC-MS (113,000), and 14,000 articles on ICP-MS were found. In the period 1995-2023, the yearly publication rate accounted for 3042 for GC-MS articles and 3908 for LC-MS articles (LC-MS/GC-MS ratio, 1.3:1). Our study reveals that GC-MS/MS, LC-MS/MS, and their high-resolution variants are indispensable instrumentations in clinical science including clinical pharmacology, internal and forensic medicine, and doping control. Long-tradition manufacturers of analytical instruments continue to provide increasingly customer-friendly GC-MS and LC-MS apparatus, enabling fulfillment of current requirements and needs in the life sciences. Quantitative GC-MS and GC-MS/MS methods are expected to be used worldwide hand in hand with LC-MS/MS, with ICP-MS closing the gap left for metal ions. The significance of analytical chemistry in clinical science in academia and industry is essential.

Keywords: analytical chemistry; clinical medicine; gas chromatography; life sciences; liquid chromatography; mass spectrometry.

Figure 1

Simplified schematic presentation of modern quadrupole (Q)-based (A) gas chromatograph-mass spectrometers (GC-MS) and (B) gas chromatograph-tandem mass spectrometers (GC-MS/MS). In LC-MS and LC-MS/MS, a liquid chromatograph (LC) is used instead of a gas chromatograph (GC), and electrospray ionization is applied instead of chemical ionization or electron ionization (no use of reagent gases).

Figure 2

Original graphs showing the time course of publications found in PubMed by using the search terms “GC-MS” (left panel, 102,734 in total), “LC-MS” (middle panel, 113,171 in total), “ICP-MS” (right panel, 13,628). Retrieved on 13 November 2024.

Figure 3

Time-course of publications found in PubMed by using the search terms “GC-MS[Title/Abstract]” and “LC-MS-MS[Title/Abstract].” Data were exported from PubMed and analyzed by GraphPad Prism 7.0 (GraphPad Software, San Diego, CA, USA). Retrieved on 17 August 2024.

Figure 4

Comparison of measurements of anandamide (AEA) in 277 human plasma samples from a previously reported clinical trial performed by GC-MS/MS (method B) and LC-MS/MS (method A). LC-MS/MS analyses were performed about one year after the GC-MS/MS analyses. (A) Linear regression analysis and (B) Bland-Altman approach. Samples were analyzed for AEA on the instrument model TSQ 7000 by GC-MS/MS [29] and on the instrument model Xevo LC-MS/MS [28].

Figure 5

Study design on the effects of metformin and L-citrulline (for six weeks) and their combination (for six weeks) in patients with Becker muscular dystrophy (BMD). For more details, see the text. From Baskal et al., 2022 [30]; see also Hanff et al., 2018 [31].

Figure 6

Plasma concentration (mean ± SEM) of (A) arginine (Arg), (B) homoarginine (hArg) and (C) asymmetric dimethylarginine (ADMA), and (D) plasma hArg/ADMA molar ratio at the start (0 min) and the end (30 min) of the L-arginine infusion (0.5 g/kg body weight) into 11 children, and at the indicated time points thereafter. Arg, hArg, and ADMA were measured by GC-MS-based methods. From Ref. [32].