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EC number: 208-762-8
CAS number: 540-97-6
At GD 19 (Group A rabbit), the Cmaxfor parent D6 was determined to be 6
hours post-dosing and levels dropped off at 12-48 hours
post-dosing. Based on Group A rabbit results, it appeared that
steady-state would be reached in the time frame of the next study (i.e.
developmental range finder with estimation of KMD).
Whole blood, RBC and plasma 14C-activity time-courses were determined
for Group 1 animals dosed on GD26. Excretion in urine and feces was
followed up to 48 hours. The 14C-activity concentrations (µg-eq/g) in
blood, plasma and RBC for the two rabbits dosed with 14C-D6 were still
increasing at 48 hours (GD 28) post-dosing. The plasma time course of
parent D6 concentrations followed the time course of radioactivity
concentrations on GD 26-28.
Orally administered 14C-D6 was slowly absorbed. The maximum blood,
plasma or RBC concentration (Cmax) was achieved at 24 or 48-hours
post-dosing. All three sample matrices plateaued or were increasing,
thus absorption and elimination rates could not be
calculated. Concentrations of time-course radioactivity in whole blood
were similar to that detected in plasma and RBC. The AUC of the
radioactivity in the non-pregnant rabbit was lower in whole blood than
in plasma, but similar in the pregnant rabbit. The14C-activity AUC was
~2 to 2.5-fold less in the pregnant rabbit vs. the non-pregnant rabbit
in both the plasma and blood, but equivalent in the RBC.
Based only on urine/rinse data, 2% of the administered dose was absorbed
(and eliminated in the urine). A mass balance was not conducted in this
study since carcass and tissues were not analysed for radioactivity;
therefore the total percent absorbed in the study cannot be
determined. Feces contained the majority of the administered dose at
~56%. Since rabbits are known to ingest their night feces, there is the
possibility that D6 blood levels reflected the re-ingestion of D6. The %
administered dose recovered in the urine and feces were similar between
the pregnant and non-pregnant rabbits in Group 1.
Parent D6 was detected in Group 1 plasma samples with levels above the
limit of quantitation (LOQ) beginning at 2 hours until sacrifice at 48
hours post-dosing. In the Group 1 rabbit plasma samples, parent D6
follows the same pattern as radioactivity, where the highest
concentration was at 48 hours. The radioactivity in the collected Cmax
plasma samples was low and profiling and metabolite identification was
not conducted. Based on the Group 1 rabbit D6 blood concentration time
course, steady-state would not be reached in 20 days of a repeated dose
Comparison of the plasma time-course for14C-activity and parent D6 gives
insight that metabolism is occurring. Plasma parent D6 AUCs were
calculated and compared to14C-activity AUCs and the difference in these
AUCs for each animal suggest metabolism. With only two animals in Group
1, with one being pregnant and the other non-pregnant, it is difficult
to draw conclusions regarding whether metabolism differs with pregnancy
Dose (Concentration, Administration and Recovery of the Administered
The concentration of total test material in each dose preparation was
within 102-110% of the target concentration. The concentration of
radioactivity in the dose preparations for Group 1 was 75.3% of the
At the time of test material administration, the body weights of the
female rabbits averaged 3.2 kg. The administered dose of 12C-D6 with or
without 14C-D6 administered to various groups ranged from 460-494 mg/kg
bw for the targeted 450 mg/kg bw dose. A mean range of 338-340 µCi/kg
bw (or ~1097-1143 µCi per rabbit) was administered to Group 1 rabbits of
the 450 mg/kg bw oral dose groups. The actual radioactivity
administered to rabbits through oral dosing was slightly less than the
targeted dose range of ~400 µCi/kg bw. The difference between the
target and actual doses administered had no effects on the results of
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