Absorption, distribution, metabolism, and excretion of 14C-RDX following oral administration to minipigs (DAAD05-02-P-2319)
Musick, TJ; Berge, MA; Patzer, SS; Tilch, KR
HERO ID
672734
Reference Type
Technical Report
Year
2010
Language
English
| HERO ID | 672734 |
|---|---|
| Year | 2010 |
| Title | Absorption, distribution, metabolism, and excretion of 14C-RDX following oral administration to minipigs (DAAD05-02-P-2319) |
| Authors | Musick, TJ; Berge, MA; Patzer, SS; Tilch, KR |
| Publisher Text | Covance Laboratories Inc. |
| City | Madison, WI |
| Abstract | The tissue distribution. elimination, and metabolism of radioactivity were examined following a single oral administration of 14C-RDX, at a target dose of 45 mg/kg, to male and female Yucatan minipigs. Blood, urine, and feces were collected through 24 hours postdose. Blood, plasma, selected tissues, urine, and feces were analyzed for total radioactivity. Following dose administration, all animals vomited. Animals vomited at various times over the course of the study. Concentrations of 14C-RDX-derived radioactivity in plasma reached maximum levels (Cmax) at 12 hours postdose for both males and one female. Blood and plasma concentrations for the second female reached Cmax at 6 hours postdose. The plasma Cmax values for males ranged from 8.76 to 18.3 ug equivalents 14C-RDX/g, and in females values ranged from 8.54 to 10.0 ug equivalents 14C-RDX/g. The distribution of 14C-RDX-derived radioactivity was extensive, with drug derived radioactivity quantifiable in all analyzed tissues at 24 hours postdose. The highest concentrations of radioactivity were observed in liver, kidneys, and small intestine. The lowest values were observed in abdominal fat, skeletal muscle, and skin. Quantifiable levels of radioactivity in the brain and testes suggest 14C RDX derived radioactivity crosses the blood/brain and blood/testes barriers. Urine was the major route of elimination of 14C-RDX-derived radioactivity. At 24 hours postdose, urine and feces accounted for average values of 17.3 and 0.53% of the dosed radioactivity, respectively, in males and in females accounted for average values of 16.0 and 0.79% of the dosed radioactivity, respectively. The overall excretion recoveries in males and females were 40.6 and 29.7%, respectively. The relatively low levels of radioactivity observed in gastrointestinal contents and wash as well as low levels in feces suggest nearly complete oral absorption of 14C-RDX-derived radioactivity. Metabolite profiling and LC/MS/MS showed quantifiable levels of metabolites M1 (4-nitro-2,4-diazabutanal), M2 (4-nitro-2,4-diaza-butanamide), and parent RDX. All three metabolites were observed in urine, only RDX was observed in plasma. LC/MS/MS analysis of plasma showed trace amounts of RDX metabolites MNX, DNX, and TNX. Analysis also showed trace amounts of the metabolites MNX and DNX in male urine and MNX in female urine. RDX concentrations in the brains ranged from 33.5 to 1070 ng/g. RDX concentrations in liver were less than 1 ng/g. |
| Report Number | ADA526472 |
| Url | http://www.dtic.mil/cgi-bin/GetTRDoc?AD=ADA526472 |
| Is Certified Translation | No |
| Dupe Override | No |
| Number Of Pages | 147 |
| Is Public | Yes |
| Language Text | English |