Accelerator Mass Spectrometry (AMS) provides quantitative sensitivity towards molecularly equivalent radiotracers (14C) down to concentrations not accessible by other forms of mass spectrometry. Accordingly, drug studies are possible with low or sub-microgram doses (dubbed microdosing when applied in a pharmacological context). The utility of AMS, however, is not limited to microdosing; the ability to trace compounds that are extremely small in terms of mass and radioactivity can stimulate drug development in other ways. One such area pertains to biomolecules that are difficult or prohibitively expensive to radiolabel. We report results of two such studies. In either case, their chemical complexity precluded affordable chemical synthesis; therefore, small-scale biosynthetic approaches were employed Experiments: For a first example, we show the systemic exposure of a bacterial glycolipid drug candidate in rats following intranasal (IN) and intravenous administration (IV). This radiotracer was obtained from a bacterial fermenter using a non-specific 14C-labeled carbon source; the final specific activity and mass yield were too low to permit animal testing using beta detectors. AMS sensitivity, however, enabled a full tissue distribution study (brain, spleen, liver, kidney, etc....) of this drug substance in 7 rats using 20 (IV) and 2000 (IN) picoCuries of the experimental compound. In a second example, details of the human biokinetics of 14C-Vitamin B12, arguably nature's most complex small molecule is presented. The molecule was obtained using a microscale radiolabel synthesis in Salmonella Typhimurium. A specific activity of 60 Ci/mol proved efficient incorporation of an advanced metabolic precursor that contained 1 radiolabel per molecule. The labeled B12 material was purified and a human kinetic study performed using a physiological dose (2.5 microgram, 100 nanoCuire). Results/Conclusion: AMS enables early animal and human testing of complex natural or recombinant products using 'benchtop' sized biolabeling equipment. Accordingly, metabolic profiles can be established without significant capital outlay for custom syntheses.
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