Radiokinetics and Mass Balance in Dogs

To evaluate the pattern and the rate of excretion and to investigate the time course of radioactivity concentrations in blood and plasma with the aim of getting information about the absorption process, the AUC, Cmax and the elimination half-life of radioactivity in blood and plasma. Possibly, indices for enterohepatic 

The route of administration projected to be used therapeutically should be applied. If possible - and the solubility of the drug allows - the study should also be performed after intravenous administration. The results of both routes should be compared. Since the oral administration is the most prominent route of administration, this route is described here. The method can be adapted for other routes of administration. 

Normally, the radiokinetic study is performed administering a single dose per administration route. In case of extraordinary circumstances, for instance when there is a suspicion of an accumulation of any metabolite, a radiokinetic study with repeated dosing can be considered. 

Three healthy male beagles receive an intravenous dose into a jugular vein or into the vena cephalica antebrachii (typically 1-5 mg/kg b.w.). After a wash out period dependent on the duration of excretion of the drug/metabolites (typically 4 weeks at minimum), the same animals are dosed orally by using a stomach tube (typical dose 10 mg/kg b.w.). Normally, 5-10 MBq/animal is a sufficient radioactive dose for a 14C-label, in case of 3H about 50 MBq/animal could be used. Up to 168 h after administration, blood, urine and feces are collected. At each collection time about 3.5 mL of blood are taken for radioanalysis (2-3 aliquots) and for processing plasma for subsequent radio- and bioanalysis in plasma (also 2-3 aliquots each). The plasma is aliquoted immediately after centrifugation without warm-up. At a few preselected time points additional blood is collected for metabolite investigations (about 5 mL). 

Radioanalysis is performed by the liquid scintillation procedure either directly after addition of a scintillator (urine, cage washing) or following combustion and addition of a scintillator (blood, plasma, feces). 

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AVE 3559 was developed for the treatment of obe-sitas. It was 14C-labeled and investigated in a dog radiokinetic study to determine the time course of radioactivity concentrations in blood/plasma and to determine the pattern and rate of excretion, the residual concentrations at the end of the study 168 h after administration and the mass balance following oral and intravenous route of administration. 

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