Tissue distribution and elimination of N-methyl-N-2,4,6-tetranitroaniline (tetryl) in rats.
The elimination of tetryl was studied using ring-labeled 14C-tetryl. Tetryl was given subcutaneously to male Sprague-Dawley rats at doses of 25, 100, and 300 mg kg(-1), and urine and feces were collected 24 h post-injection. Percent urinary elimination was observed to be 10.02 +/- 2.48, 11.2 +/- 1.66, and 13.24 +/- 5.79 (mean +/- SEM) respectively. Percent fecal elimination was 15.68 +/- 6.13, 9.41 +/- 1.52, and 8.45 +/- 1.81 respectively. At 24 h post-injection, tissues from male Sprague-Dawley rats were collected from animals that received 100 mg kg(-1) 14C-tetryl. Tetryl was found to be poorly absorbed with approximately 65% of the administered dose remaining at the site of subcutaneous injection. Blood was found to be the principal depot of radioactivity, followed by muscle, liver, and kidney. Analysis of the tissue to blood radioactivity ratio revealed that the liver had the highest ratio (1.2), followed by brain (0.45), kidney (0.38), and testes (0.35). All other tissues analyzed had ratios less than 0.30. Urine of animals receiving 14C-tetryl (100 mg kg(-1)) was analyzed using HPLC coupled with UV detection (200-600 nm; 1.2 nm resolution). During HPLC analysis, 1 min fractions were collected and radioactivity measured. Two major peaks of radioactivity were identified at approximately 5 and 14 min retention times, respectively. The 14 min peak had the same retention time and UV spectrum as picric acid and 5 min peak had the same retention time and UV profile as picramic acid. The data presented demonstrates that that there is little retention of tetryl in specific tissue depots and that tetryl is eliminated in roughly equal amounts in both urine and feces. The major urinary metabolites identified picric acid and picramic acid (a known urinary metabolite observed in rabbits). From microsomal fraction studies, a major metabolite, NMPA, was identified. The formation of this metabolite was found to be dependent on at least two enzymes. One enzyme is dependent on NAD+ for NMPA formation and is likely to be NADP(H):quinone oxidoreductase. The second metabolite is NADP+ dependent and is probably related to NADPH:cytochrome-P450 reductase.
Department of Pharmacology and Toxicology, University of Louisville School of Medicine, 500 South Preston St, Louisville, KY 40292, USA. sr.myers@louisville.edu
Steven R
SR
Myers
Joseph A
JA
Spinnato
D000814:Aniline Compounds / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000818:Animals; D001921:Brain / Q000378:metabolism; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005243:Feces / Q000737:chemistry; D007279:Injections, Subcutaneous; D007408:Intestinal Absorption; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D015394:Molecular Structure; D009578:Nitrobenzenes / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D013737:Testis / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution
D000814:Aniline Compounds; D002250:Carbon Radioisotopes; D009578:Nitrobenzenes; C015384:nitramine