Use of Accelerator Mass Spectrometry in Human Health and Molecular Toxicology

Abstract

Accelerator Mass Spectrometry (AMS) has been adopted as a powerful bio-analytical method for human studies in the areas of pharmacology and toxicology. The exquisite sensitivity (10−18 mol) of AMS has facilitated studies of toxins and drugs at environmentally and physiologically relevant concentrations in humans. Such studies include: risk assessment of environmental toxicants, drug candidate selection, absolute bioavailability determination, and more recently, assessment of drug-target binding as a biomarker of response to chemotherapy. Combining AMS with complementary capabilities such as high performance liquid chromatography (HPLC) can maximize data within a single experiment and provide additional insight when assessing drugs and toxins, such as metabolic profiling. Recent advances in the AMS technology at Lawrence Livermore National Laboratory have allowed for direct coupling of AMS with complementary capabilities such as HPLC via a liquid sample moving wire interface, offering greater sensitivity compared to graphite-based analysis therefore, enabling the use of lower 14C and chemical doses, which are imperative for clinical testing. The aim of this review is to highlight the recent efforts in human studies using AMS, including technological advancements and discussion of the continued promise of AMS for innovative clinical based research.

Toxicokinetics of benzo[a]pyrene in humans: Extensive metabolism as determined by UPLC-accelerator mass spectrometry following oral micro-dosing

“…Accelerator mass spectrometry (AMS), due to its remarkable sensitivity to 14 C, is finding increasing use in study of environmental carcinogens (Enright et al, 2016;Felton and Turteltabaub, 1994;Ognibene et al, 2004). Human subjects have been dosed with [ 14 C]labeled 2-amino-3-methylimidazo[4,5-f]quinolone (IQ), 2-amino-3,8-dimethylimidazo[4,5b]quinoxaline (MeIQx), 2-amino-3-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), tamoxifen, aflatoxin B 1 , dibenzo [def,p]chrysene (DBC) and BaP (Brown et al, 2006;Enright et al, 2016;Hummel et al, 2018;Jubert et al, 2009;Lightfoot et al, 2000;Madeen et al, 2015;. The majority of these studies with carcinogens have assayed for target organ DNA binding (Lightfoot et al, 2000;Felton and Turteltaub, 1994) (dosing prior to surgical resection) but some have examined pharmacokinetics (Hummel et al, 2018;Madeen et al, 2015;.…”

Synthesis of carbon‐14–labelled peptides

“…The specific activity can be adjusted by diluting with unlabelled material. Also, this limitation of using 14 C can be overcome through the use of accelerated mass spectrometry (AMS) during metabolite studies . The methodology to the synthesis of a 14 C‐labelled peptide is shown in Figure .…”

Nanotracing and cavity-ring down spectroscopy: A new ultrasensitive approach in large molecule drug disposition studies

“…Radioisotopic labeling, especially with radiocarbon, is an excellent tool in pharmaceutical science and has widespread utility in absorption, distribution, metabolism and elimination (ADME) studies in preclinical species and man [ 1 ]. There is also a growing list of applications of 14 C-microdosing and low-level (< 1 μCi) radiotracer/ADME studies to address pharmacokinetics, absolute bioavailability, drug-drug interaction and pharmacodynamics questions for early translational research to man [ 2 , 3 , 4 ]. The familiar, analytical tools are 11 C positron emission tomography, scintillation counting, and accelerator mass spectrometry (AMS) for carbon- 14 C radiolabeled compounds [ 5 ].…”