PARENT SESSION
1:30 PM to 3:30 PM
Sunday, April 21, 2002
Poster Session 7 Radioprotectors
Room: Nevada Exhibition Center
(P12-112) Pharmacokinetics and survival in mice implanted with biodegradable amifostine pellets or injected with free amifostine.
Srinivasan, Venkataraman*,1, Pendergrass, James1, Kumar, K. Sree1, Seed, Thomas1, 1 Radiation Casualty Management Team, Bethesda, MD
ABSTRACT-
Biodegradable, implantable amifostine pellets were tested in mice to evaluate the drug's radioprotective efficacy and toxicity. Blood levels of WR-1065, the active metabolite of amifostine, were measured in mice that either were given 600 mg/kg of free amifostine (sc) or had the equivalent dose in pellet form. In the free amifostine group, the peak level (462 ±59 nmole/ml blood) was observed 30 min after injection; in the amifostine pellet group, the peak level (127 ±42 nmole/ml blood) occurred at 60 min; the blood values remained high up to 3 hr thereafter. Total calculated releases (area under the curve) were similar for both groups. Thirty-day survival in mice implanted with 1, 2, or 3 pellets 2 hr prior to 60Co gamma radiation of 10, 11, and 15 Gy, respectively, were 25%, 100%, and 62.5%, respectively. To identify the correlation between blood WR-1065 and survival, doses of 25, 50, and 100 mg/kg of free amifostine were administered to groups of mice at selected times. One group was irradiated at 10 Gy, and 30-day survival monitored. Unirradiated mice from another group were used to determine blood WR-1065 concentrations. We found that 40 nmole of WR-1065/ml of blood correlates with 100% survival at 10 Gy. In conclusion, biodegradable, implantable amifostine pellets provided sustained radioprotection, however, the present pellet formulation provided two types of drug release kinetics (early-bolus and sustained) and hence reformulation of the amifostine pellets is required to perform correlation studies that may achieve even lower blood levels of WR-1065 promoting radioprotective efficacy.
KEYWORDS: radioprotection, amifostine, drug delivery, biodegradable implants