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Accelerator Mass Spectrometry (AMS) is an exceptionally sensitive method of isotope detection. For analysis of samples generated in ADMET studies, AMS is used in place of radioactivity measurement (liquid scintillation counting, or LSC) to quantitate carbon-14 when limits of detection lower than those achievable by LSC are required. The value of improved sensitivity for investigations of pharmacokinetics, metabolite profiles, mass balance and toxicology are widely recognized, but implementation of AMS in these analyses has been impeded by the low throughput of sample preparation, the standard methods comprising manual operations that are not amenable to automation. We have addressed the issue of sample preparation by creating a front-end for the AMS instrument that transforms liquid samples to gaseous carbon dioxide in a rapid, on-line mode of operation. The apparatus is a chamber connected by tubing to the gas-accepting ion source of the AMS instrument, within which is contained an addressable cassette that carries thermally insulated deposits of copper oxide (for sample oxidation) at each sample location. In operation, liquid samples are deposited on the CuO (and dried) prior to placement of the cassette into the chamber. Combustion is effected by heating the CuO with an incident beam of infrared laser light and a flow of carrier gas through the chamber transports the combustion products to the AMS instrument for isotope analysis. This approach to sample processing has been evaluated using a variety of different samples generated in several model ADMET studies, including pharmacokinetics of acetaminophen in the rat, HPLC analysis of in vivo acetaminophen metabolites and in vitro testosterone metabolites, drug-DNA interactions in cells in culture and in orthotopic tumor models, and carcinogen-DNA binding in cultured cells. Our combined sample combustion apparatus and AMS instrument currently provide limits of detection of 0.5 attomoles and five times Modern for low isotope ratio samples.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]