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EC number: -
CAS number: -
The adsorption, distribution, metabolism and excretion of EXP0700332 has
been investigated in the rat using [14C]-labelled EXP0700332.
Pharmacokinetic, excretion/balance and tissue distribution experiments
were conducted on samples generated after a single oral administration
of [14C]-labelled EXP0700332 to rats at 30 mg and 300 mg/kg and a
repeated oral administration of [14C]-labelled EXP0700332 at 30 mg/kg.
Selected samples of faeces were chromatographically analysed to examine
the nature of radioactive components.
Maximum mean plasma total radioactivity concentrations were observed at
4 hours post oral dose (30 mg/kg, both sexes) administration and at 1
and 6 hours following oral dose (300 mg/kg, male and female rats,
respectively) administration. Concentrations declined rapidly thereafter
with apparent half-lives of ca. 25 hours. Systemic exposure to the total
radioactivity (AUC0-72) was <16 µg equivalents/g (30 mg/kg dose group)
and <123 µg equivalents/g (300 mg/kg dose group). Mean total
concentrations of radioactivity were at levels below 0.075 µg
equivalents/g (30 mg/kg) and below 0.4 µg equivalents/g (300 mg/kg) at
72 hours dose. The apparently low absorption and rapid elimination of
radioactivity is further supported by the excretion balance results
The mean pharmacokinetic parameters (total radioactivity) obtained in
plasma following seven consecutive oral doses of [14C]-labelled
EXP0700332 to male rats at a dose level of 30 mg/kg/day showed similar
pharmacokinetic parameters to that obtained following single dose
Excretion of administered radioactivity in the 168 hours after both
single and repeated oral administration of [14C]-labelled EXP0700332 was
almost exclusively via the faecal route in both sexes. Urine accounted
for a smaller proportion of radioactivity (ca.1 % for each
animal) with remaining concentrations of radioactivity measured in the
cage washings and carcass. The mean total recovery of radioactivity
ranged from 83 - 106% (n = 19 animals). Although greater than 90%
recovery of radioactivity has not been achieved for all animals in this
study, this can potentially be explained by the fact that the majority
of the faecal radioactivity is eliminated in one sample and therefore
obtaining a truly homogeneous sample for determination of radioactive
content is challenging. In order to perform the quantitative
radiochemical analysis on the faeces sample, small replicate subsamples
were taken (ca.0.2g) which contained very high levels of
radioactivity. It is assumed that any small analytical/experimental
error in either value could produce an artificially low recovery of
The mean proportions of the administered radioactivity recovered from
bile cannulated male and female rats during the 48 hour period following
a single oral administration of [14C]-labelled EXP0700332 at a dose
level of 30 mg/kg show a similar pattern of excretion with =1.2%
recovered in the bile.
Although greater than 90% recovery of radioactivity has not been
achieved for all animals in this study, this can potentially be
explained by the fact that the majority of the faecal radioactivity is
eliminated in one sample and therefore obtaining a truly homogeneous
sample for determination of radioactive content is challenging.
Following a single oral administration of [14C]-labelled EXP0700332 at a
dose level of 30 mg/kg to male Sprague Dawley rats shows limited
distribution of radioactivity in tissues. The majority of radioactivity
was detectable in components of the gastro-intestinal tract and other
tissues associated with elimination. Radioactivity concentrations were
at levels below the limit of detection in all tissues at 168 hours post
dose, which further supports the data obtained during the excretion
balance phase to show that elimination of total radioactivity is
essentially complete by this time point.
Qualitative assessment of the HPLC radiochromatograms obtained for all
faeces samples analysed showed minimal change in HPLC profile, compared
to that obtained for the dose formulation.
Study conducted to GLP and in accordance with the OECD 417 guideline.
Quantitative whole body autoradiography demonstrated slow absorption and
little distribution of [14C]-labelled EXP0700332. Most of the material
remained in the gastrointestinal tract, with little distribution to
organs not associated with elimination. Even the repeat oral dose study
did not show a significant increase in absorption or distribution of the
test material. For all dosing strategies, seven days after dosing via
oral gavage the radioactivty was below the limit of accurate
All these results demonstrate very low uptake and fast elimination
via the oral route up to the tested dose of 300 mg/kg.day.
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