Automated Combustion Accelerator Mass Spectrometry for the Analysis of Biomedical Samples in the Low Attomole Range

Abstract

The increasing role of accelerator mass spectrometry (AMS) in biomedical research necessitates modernization of the traditional sample handling process. AMS was originally developed and used for carbon dating, therefore focusing on a very high precision but with a comparably low sample throughput. Here, we describe the combination of automated sample combustion with an elemental analyzer (EA) online coupled to an AMS via a dedicated interface. This setup allows direct radiocarbon measurements for over 70 samples daily by AMS. No sample processing is required apart from the pipetting of the sample into a tin foil cup, which is placed in the carousel of the EA. In our system, up to 200 AMS analyses are performed automatically without the need for manual interventions. We present results on the direct total (14)C count measurements in <2 μL human plasma samples. The method shows linearity over a range of 0.65-821 mBq/mL, with a lower limit of quantification of 0.65 mBq/mL (corresponding to 0.67 amol for acetaminophen). At these extremely low levels of activity, it becomes important to quantify plasma specific carbon percentages. This carbon percentage is automatically generated upon combustion of a sample on the EA. Apparent advantages of the present approach include complete omission of sample preparation (reduced hands-on time) and fully automated sample analysis. These improvements clearly stimulate the standard incorporation of microtracer research in the drug development process. In combination with the particularly low sample volumes required and extreme sensitivity, AMS strongly improves its position as a bioanalysis method.

Observational infant exploratory [14C]‐paracetamol pharmacokinetic microdose/therapeutic dose study with accelerator mass spectrometry bioanalysis

“…The results of the PK NCA conducted with the i.v. microtracer mixed with a therapeutic dose were similar, but not identical, to the results from a similar NCA conducted with unlabelled PARA . Time to C max was slightly longer in this study and t 1/2 was slightly shorter in this study.…”

A Decade in the MIST: Learnings from Investigations of Drug Metabolites in Drug Development under the “Metabolites in Safety Testing” Regulatory Guidance

“…Sample graphitization is a relatively labor intensive procedure and recent developments in sample processing have resulted in faster sample turnaround times (van Duijn et al, 2014).…”

Opportunities in Low-Level Radiocarbon Microtracing: Applications and New Technology

“…We know of several facilities that have implemented various levels of automation through direct analysis of CO 2 , but, for the purposes of this paper, the activities of the AMS group at TNO in the Netherlands well exemplify the state of the art for automation as applied to a bio-AMS oratory [74]. …”