Metabolite profiling of [14C]hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) in Yucatan miniature pigs.
The study reported herein examined the metabolism of 14C-labeled hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) resulting from a single oral gavage of 5 ml/kg to male and female Yucatan miniature pigs (43 mg/kg, 56 microCi/kg in 0.5% carboxymethylcellulose in water). Blood, urine, and feces were collected at selected times of 1, 6, 12, and 24 h postdose. At 24 h postdose, liver samples were collected. Blood, plasma, liver, and excreta were analyzed for total RDX-derived radioactivity and metabolites were identified. Urine was the major route of elimination of 14C-RDX-derived radioactivity in both males and females. Relatively low levels of radioactivity were found in gastrointestinal contents and in feces, suggesting nearly complete absorption of 14C-RDX following an oral dose. Analysis of urine by liquid chromatography-mass spectrometry (LC/MS) identified quantifiable levels of two ring-cleavage metabolites, 4-nitro-2,4-diazabutanal and 4-nitro-2,4-diaza-butanamide, as well as parent RDX. The 4-nitro-2,4-diazabutanal, was seen in earlier studies of aerobic metabolism of RDX. The 4-nitro-2,4-diaza-butanamide, an amide, was not previously reported but was tentatively identified in this study. Analysis by a more sensitive method (LC/MS/MS) also showed trace amounts of the RDX metabolites 1-nitroso-3,5-dinitro-1,3,5-triazacyclohexane (MNX) (in both male and female urine) and 1-nitro-3,5-dinitroso-1,3,5-triazacyclohexane (DNX) (in male urine). Analysis of plasma by LC/MS/MS also revealed quantifiable levels of RDX and trace levels of MNX, DNX, and 1,3,5-trinitroso-1,3,5-triazacyclohexane (TNX). None of the liver extracts showed quantifiable levels of RDX or any identifiable metabolites. Most of the radioactivity was in the form of water-soluble high-molecular-weight compounds. RDX when given orally to pigs was rapidly metabolized by loss of two nitro groups followed by ring cleavage.
Major
Michael A
MA
Directorate Toxicology, U.S. Army Center for Health Promotion and Preventive Medicine, Aberdeen Proving Ground, Maryland 21010-5403, USA. michael.major@us.army.mil
Reddy
Gunda
G
Berge
Milan A
MA
Patzer
Shari S
SS
Li
Austin C
AC
Gohdes
Mark
M
D000818:Animals; D002247:Carbon Isotopes; D002853:Chromatography, Liquid; D053834:Explosive Agents / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D008099:Liver / Q000378:metabolism; D013058:Mass Spectrometry; D008970:Molecular Weight; D012989:Soil Pollutants / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D013552:Swine; D013556:Swine, Miniature; D014227:Triazines / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity
D002247:Carbon Isotopes; D053834:Explosive Agents; D012989:Soil Pollutants; D014227:Triazines; C009160:cyclonite