Radioprotection, pharmacokinetic and behavioural studies in mouse implanted with biodegradable drug (amifostine) pellets.
OBJECTIVE
We evaluated the use of a subcutaneously (s.c.) implantable, biodegradable pellet as a drug delivery system for the radioprotector amifostine.


METHODS
Mice were implanted s.c. with either the custom-made biodegradable amifostine drug pellet or the placebo pellet without amifostine, exposed to cobalt-60 gamma-radiation (bilateral, 1 Gy min(-1), 7-16 Gy), and the 30-day survival rate was monitored. The non-irradiated mouse was used for pharmacokinetic and behavioural tests.


RESULTS
Significant radioprotection (85-95% survival) at 10 Gy was observed in the three-amifostine pellet implanted group 3-5 h after implantation. LD50/30 was 7.97, 8.74 and 16.64 Gy for the control, three-placebo pellet (dose reduction factor, DRF=1.10, p<0.01), and three-amifostine pellet (DRF=1.79, p<0.01) groups respectively in mouse exposed to radiation 2h after implantation. Radioprotection at 12 Gy was observed up to 4h after s.c. amifostine administration and up to 3h after implantation. Pharmacokinetic data revealed that the three-amifostine pellet group had sustained blood WR-1065 levels at 2 h after implantation, in contrast to the reported sharp peak at 30 min for s.c. administration. Although locomotor activity was significantly reduced (p<0.01) in the amifostine pellet group, the onset of the locomotor decrement was delayed as compared with groups that received 400 and 750 mg kg(-1) s.c. amifostine.


CONCLUSIONS
Amifostine in biodegradable implant was effective. The radioprotection observed was comparable between conventional s.c. administration of the drug and implantation. Pharmacokinetic data and locomotor activity suggest that the implantation was beneficial though radioprotection data warrants formulation improvements in implants.
Srinivasan
V
V
Radiation Casualty Management Team, Radiation Medicine Department, Armed Forces Radiobiology Research Institute, Bethesda, MD 20889-5603, USA. srinivasan@afrri.usuhs.mil
Pendergrass
J A
JA
Kumar
K S
KS
Landauer
M R
MR
Seed
T M
TM
D004999:Amifostine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000818:Animals; D004343:Drug Implants; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects* / Q000528:radiation effects*; D011837:Radiation-Protective Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics
D004343:Drug Implants; D011837:Radiation-Protective Agents; D004999:Amifostine