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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 obtained.
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 administration.
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 radioactivity.
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.
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