Bioanalytics for Human Microdosing

Abstract

Low drug doses used in microdose or phase 0 studies present quantitation challenges to routine bioanalytical methods. Liquid chromatography‐mass spectrometry (LC‐MS), accelerator mass spectrometry (AMS), and positron emission tomography (PET) are bioanalytical techniques used for analysis of phase 0 samples. LC‐MS is most common and generally preferred if drug and metabolite concentrations are not low. AMS has the best sensitivity and precision, while PET provides images of distribution in vivo .

GAS-HYBRID SOURCE 14C-AMS:Application to terrestrial ecosystem, biological, and environmental research

“…Similar tracer-based studies could be applied to further elucidate the intersection of form and function in the stabilization of organic matter in soil pools (Figure 3). (including biomedicine) and have been used to explore metabolism and kinetics [e.g., Buchholz et al, 1999;Cleland 2003;Turtletaub et al, 1990;Vogel and Love, 2005], DNA damage [e.g., Dingley et al, 1998] and the potential of chemical therapeutics [e.g., Buchholz et al, 2012]. Targeted labeling using radiocarbon ( 14 C) allows for the calculation of metabolite fluxes through specific pathways in the presence of multiple carbon sources [e.g., Stewart et al, 2010] and provides a means to independently test and constrain FBA models.…”

“…Due to atmospheric weapons testing activities the amount of 14 C in the atmosphere doubled in the mid/late 1950s and early 1960s from its preindustrial value of 14 C/ 12 C ratio of 1.176x10 -12 [e.g., Nydal and Lovseth, 1983]. Following the atmospheric weapons test ban in 1963, the 14 C/ 12 C ratio, has decreased ( Figure 1) due to the net isotopic exchange between the atmosphere, ocean and terrestrial biosphere [e.g., Levin and Hessheimer, 2000;Graven et al, 2011;2012] and a dilution effect due to the burning of 14 C-free fossil fuel carbon, the "Suess Effect" [e.g., Suess, 1955;Stuiver and Quay, 1981]. Germany/Austria [Levin, assorted] Wellington NZ [Manning et al, ] La Jolla (CA) [Graven et al, 2012] NH annual [Stuiver and Quay, 1981] North Pacific gyre [Guilderson et al, in prep] South Pacific gyre [Guilderson et al, 2000] Except for the fact that the radiocarbon slowly decays, molecules that contain radiocarbon exactly behave chemically the same as its stable brethren:…”

Directly Coupled High-Performance Liquid Chromatography–Accelerator Mass Spectrometry Measurement of Chemically Modified Protein and Peptides

“…12,13 , 14 C-AMS is an attractive approach for quantitation of therapeutic proteins or low-abundance post-translational modifications displayed on proteins because its sensitivity allows the use of doses that impose negligible chemical and radioactive risk to humans, while providing robust quantitative data. 14,15 …”

“…Carbon-14 accelerator mass spectrometry ( 14 C-AMS) has been used for a wide variety of biological experiments including measurement of drugs and their metabolites, , bioavailability determination of dietary components, and detection of protein − and DNA adducts , formed by reactive compounds. Experiments using 14 C-AMS have proven useful in predicting pharmacokinetic properties of several drugs. − In addition, measurement of protein therapeutics in experimental animals using 14 C-AMS has recently been reported. , 14 C-AMS is an attractive approach for quantitation of therapeutic proteins or low-abundance post-translational modifications displayed on proteins because its sensitivity allows the use of doses that impose negligible chemical and radioactive risk to humans, while providing robust quantitative data. , …”