Download Pharmacokinetics Using Carbon-14 and Cavity Ring

Pharmacokinetics Using Carbon-14 and Cavity Ring-Down Spectroscopy
A. D. McCartt, T. Ognibene, G. Bench, K. Turteltaub
Lawrence Livermore National Laboratory
Purpose
The prevalence of carbon in living organisms makes carbon-14 an ideal isotopic tracer for biological studies. In the past decades,
carbon-14 has been used in studies of pharmacology, nutrition, carcinogenesis, toxicology, and fundamental biology. For micro-tracer
studies, where small, physiologically relevant, xenobiotic doses are administered, accelerator mass spectroscopy (AMS) has been used
for carbon-14 quantification. However, AMS systems are large, complex, and costly which has limited the proliferation of carbon-14
micro-tracer techniques. For this reason several efforts have been made to develop more robust and cost effective methods of carbon14 detection.
Methods
Here we present our prototype carbon-14 cavity ring-down spectrometer (CRDS). This spectrometer was developed using simple
robust hardware for the explicit purpose of measuring carbon-14 concentrations in biological samples. This capability is demonstrated
by comparing CRDS and accelerator mass spectrometry (AMS) results. Samples from a pharmacokinetic case study using guinea pigs
as the model organism were measured with CRDS and compared to measurements made with AMS on duplicate samples. Guinea pigs
were dosed intravenously with an oxime aceteyltransferase reactivator with tissue and plasma samples taken in a geometric time
series.
Results
The Figure below plots the carbon-14 labeled oxime concentrations measured by both AMS and CRDS in guinea pig liver and plasma
samples. The measurements of carbon-14 in the guinea-pig samples by CRDS accurately reproduced the AMS results (R2=.99739 ).
Pharmacokinetic parameters have been calculated for both AMS and CRDS concentration curves and presented for comparison.
Figure Caption:Pharmacokinetic Curves. Carbon-14 concentrations for samples from a guinea-pig, animal study were measured by
AMS (blue squares) and CRDS (red circles). Data is presented in nanograms of oxime xenobiotic per milligram of sample.
Pharmacokinetic parameters were calculated for all of the curves and are presented for comparison. Error bars represent 1- σ
measurement error for a single sample. CRDS error values originate from measured shot-to-shot noise for a single carbon dioxide
sample, and AMS error values are attributed to the larger of counting statistics or variation on measurements for a single graphite
target.
Conclusion
This relatively simple CRDS instrument is capable of resolving carbon-14 concentrations below the natural abundance, and our results
suggest that it can replace AMS for most biological studies. The approach affords easy access to powerful carbon-14 tracer techniques
that can characterize complex biological systems. Carbon-14 labeling is a proven method that elegantly and quantitatively traces target
species through biochemical systems. It is highly versatile as almost all organic compounds can be labeled with carbon-14 and many
carbon-14-labeled derivative chemicals have been available for decades. Furthermore, micro-tracer techniques in humans have the
potential to greatly reduce drug development cost and expedite the realization of innovative health care practices such as personalized
medicine. Carbon-14 detection with CRDS can provide access to this simple yet powerful technique for tracking organic compounds
through biochemical systems.
Portions of the material submitted here are to be presented at the 252nd American Chemical Society National Meeting & Exposition.