Custom carbon-14:Layout 1 14/1/10 19:57 Page 54
Radiolabelling
Laboratories and Harlan, using C-14 compounds
supplied by external suppliers or internal isotope
groups. AMS analysis is performed, for example,
by Xceleron and Vitalea.
Pharmaceuticals in the environment
Given that many pharmaceuticals need to be
robust enough to pass through the stomach it is
not surprising that they find their way into the
environment via excretion and the public sewage
system. This has led to increased attention on the
environmental fate of pharmaceuticals (and other
chemicals) from regulators to identify and mitigate
possible adverse environmental effects prior to
commercialisation. Most major pharmaceutical
companies now model the environmental behav-
iour of their development compounds. It has long
been a requirement to provide environmental fate
data as part of the regulatory process for pesti-
cides. The experimental protocols used to generate
environmental fate information such as biodegra-
dation/accumulation are robust and well-validated
Figure 1 270nCi (10kBq) per individual. With such low and are set out in regulatory guidance documents,
levels it is very important to avoid any risk of C- for example OECD 308. In this guidance C-14
14 contaminants. With this in mind, test materi- radiolabelled compounds are the preferred tools to
als are best prepared at high specific activity study the degradation pathway and establish a
(~50mCi/mmol; 1.85GBq/mmol) with full analy- mass balance. More recent guidance specifically
sis including structure confirmation prior to dilu- covers chemicals found in the aqueous and sludge
tion with unlabelled material. components of sewage (OECD 314).
A few years ago all the focus for AMS was on The EMEA issued a guideline on the environ-
phase zero microdosing with drug levels at 1/100
th
mental risk assessment of medicinal products in
of the therapeutic level (cold drug) with a micro- 2006. It sets out a tiered approach: Phase I requires
tracer level of C-14 to provide a tool for quantifi- an estimate to be made of the environmental risk in
cation. Advocates of the technology now focus on the aquatic component using a predicted environ-
promoting the use of AMS to address specific mental concentration (PEC) formula. If this is trig-
problems where the added value is clear. For exam- gered then Phase IIA requires basic environmental
ple, as an add-on to a traditional Phase I study fate data in which C-14 radiolabelled compounds
where a microtracer of C-14 is used with a thera- are used in studies, which should be performed to
peutic dose. This can provide information on the Good Laboratory Practice (GLP) in line with
metabolic profile in man at a very early stage and OECD 308. These then may trigger a Phase IIB
confirm that the pre-clinical data from other data requirement.
species is representative. Specialist CROs such as Brixham
Recent literature has described use of sensitive Environmental and Battelle UK Ltd provide guid-
laser-based isotope analysis to count [C-14] ance and perform regulatory studies using carbon-
CO
2
. However, it remains to be seen if this 14 on pharmaceuticals.
offers an alternative to AMS for analysis of bio-
logical samples. Basic considerations on
As part of the IND package there is a require- radiolabelling with C-14
ment to perform a traditional human mass balance Direct irradiation of suitable nitrogen containing
study. This will usually be performed on six precursors was ruled out as a possible short-cut to
healthy male volunteers using ~100µCi (3.7MBq), carbon-14 compounds following extensive
per individual, of C-14 radiotracer. research, which found that the C-14 atom was
Pre-clinical studies using C-14 are performed by inserted randomly, in low yield, with formation of
many of the leading contract research companies extensive impurities. Thus the only practical
such as Charles River, Covance, XenoBiotic method for introduction of a C-14 label is by total
54 Drug Discovery World Winter 2009/10
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