Pushing the accelerator – speeding up drug research with accelerator mass spectrometry

Abstract

Accelerator mass spectrometry (AMS) is the most sensitive analytical method yet developed for elemental isotope analysis and has a broad range of applications. The measurement of 14C is of most interest to biomedical researchers but few studies have been reported using AMS in drug discovery and development. For biomedical use, 14C is incorporated into organic molecules by either radiosynthesis or biosynthetically and the isotope is used as a surrogate for the distribution of the radiolabelled molecule either in animal or human studies. The majority of users of 14C quantitate the radioactivity using decay counting usually with a liquid scintillation counter (LSC). Our Centre over the past 12 months has been evaluating and validating the use of AMS as an alternative detection method. In vitro spiking studies of human plasma with 14C-Fluconazole, a prescription antifungal drug has demonstrated an excellent correlation between AMS and LSC (correlation coefficient 0.999). Human Phase I clinical studies have been conducted with radioactive doses ranging from 120 Bq (7000 dpm) to 11 kBq (300 nCi) to provide mass balance, plasma concentration and radioactive metabolite profiling data. Limits of detection of 0.00022 Bq 14C-labelled drug/ml plasma have been accurately quantitated in a plasma background of 0.0078 Bq/ml (0.013 dpm/ml in a plasma background of 0.47 dpm/ml or 2.72 pMC in a background of 90.19 pMC).