Current perspectives of 14 C-isotope measurement in biomedical accelerator mass spectrometry

Abstract

Accelerator mass spectrometry (AMS) is an extremely sensitive nuclear physics technique developed in the mid-70's for radiocarbon dating of historical artefacts. The technique centres round the use of a tandem Van de Graaff accelerator to generate the potential energy to permit separation of elemental isotopes at the single atom level. AMS was first used in the early 90's for the analysis of biological samples containing enriched 14C for toxicology and cancer research. Since that time biomedical AMS has been used in the study of (1) metabolism of xenobiotics in animals and humans (2) pathways of drug metabolism (3) biomarkers (4) metabolism of endogenous molecules including vitamins (5) DNA and protein binding studies and (6) clinical diagnosis. A new drug development concept which relies on the ultrasensitivity of AMS known as human microdosing (Phase 0) is being used to obtain early human metabolism information of candidate drugs arising out of discovery. These various aspects of AMS are reviewed in this article and a perspective on future applications of AMS provided.

Metabolism and Disposition of [14C]BMS-690514, an ErbB/Vascular Endothelial Growth Factor Receptor Inhibitor, after Oral Administration to Humans

“…In our experience, traditional LSC has not consistently provided adequate sensitivity to fully characterize the PK profile of radioactivity at later time points, particularly in instances in which compounds with low specific activity were administered (Christopher et al, 2008;Zhou et al, 2010). Accelerator mass spectrometry, an ultrasensitive detection technique that relies on measurement of the 14 C/ 12 C ratio, rather than on decay counting (Lappin and Garner, 2004), can help to bridge that gap. Over the past decade, the utility of AMS has been demonstrated in several pharmacokinetic and mass balance studies (Garner et al, 2002;Beumer et al, 2007;Boddy et al, 2007).…”

Measurement of 7,8-dihydro-8-oxo-2′-deoxyguanosine metabolism in MCF-7 cells at low concentrations using accelerator mass spectrometry

“…AMS is a well established technology for radiocarbon dating and is now used for tracing 14 C-labeled compounds in biological systems (21). AMS affords subpicomole to zeptomole sensitivity in quantifying 14 C-labeled metabolites with a few percent precision, depending on experimental conditions (21,22). The method relies on measurement of 14 C in a biological sample that has been converted to solid graphite before analysis, which facilitates high measurement sensitivity because of efficient ion current production in the AMS instrument.…”

Use of Microdosing and Accelerator Mass Spectrometry To Evaluate the Pharmacokinetic Linearity of a Novel Tricyclic GyrB/ParE Inhibitor in Rats

“…Because most biological materials contain carbon, the majority of AMS studies use 14 C as the radiotracer. AMS can detect and quantify a 14 C-labeled compound in a biological matrix with 1% to 3% precision at levels ranging from approximately 10 pmol 14 C to 1 amol (1 ϫ 10 Ϫ18 ) 14 C in samples containing as little as 250 g of total carbon (12)(13)(14). More recently, methods that allow even greater sensitivity using samples as small as a few micrograms have been developed (15,16).…”