ABSTRACT
This study reports the metabolism of carbon-14labeled diisopropyl methylphosphonate (DIMP) in mink and rats, undertaken to better understand the dose-related mortality reported for mink in a previous study. In both male and female mink and rats, DIMP was rapidly absorbed after oral administration; it was metabolized by a saturable pathway to a single metabolite, isopropyl methylphosphonate (IMPA), which was rapidly excreted, primarily in the urine (90%). Fecal radioactivity, also identified as IMPA, was 1.7-3.1% of the administered dose. Female rats had a slower rate of conversion of DIMP to IMPA and less total excretion of IMPA than male rats. Metabolism of DIMP administered intravenously was not very different from that given orally in both species. These data indicate that mink absorb, metabolize, and excrete DIMP (as IMPA) in a manner very similar to mice, rats, and dogs.
Subject(s)
Organophosphorus Compounds/metabolism , Administration, Oral , Animals , Female , Injections, Intravenous , Male , Mink , Organophosphorus Compounds/blood , Organophosphorus Compounds/urine , Rats , Rats, Sprague-Dawley , Sex Factors , Species SpecificityABSTRACT
Diisopropyl methylphosphonate (DIMP), produced during manufacture of the chemical agent GB (Sarin), is a groundwater contaminant at Rocky Mountain Arsenal, Colorado. DIMP was fed for 90 days to dark brown "Ranch Wild" mink housed under controlled indoor conditions. One-year-old mink, 10 of each sex, were fed 0, 50, 450, 2700, 5400, or 8000 ppm in standard ranch diet. Actual DIMP consumption was 0, 8, 73, 400, 827, and 1136 mg/kg body wt/day, respectively. Two additional groups of 10 served as "pair-fed" controls. Body weight and food intake were recorded weekly. Complete blood count and 15 chemical analytes were measured at Weeks 0, 3, 7, and 13. Necropsy and microscopic examination were performed on all mink. No clinical morbidity or deaths occurred. Both sexes fed 8000 ppm ate approximately 20% less and weighed approximately 20% less than the controls; 5400 ppm females had a 10% weight decrement. Plasma cholinesterase (ChE) decreased in the top three dose groups starting at Week 3. At 13 weeks, decrements were approximately 50% but returned to normal after 1 week without DIMP. Erythrocyte ChE was not reduced. Heinz bodies occurred in 10-15% of RBCs in 50% of 8000 ppm mink at 13 weeks, and 0.1-2.0% of RBCs in 25% at 2700 ppm. There were mild decreases in RBC count, hematocrit, and hemoglobin, and increases in reticulocyte count, at the 5400 and 8000 ppm doses. All recovered within 3 weeks after DIMP was withdrawn. The 8000 ppm group had marginal splenic hematopoiesis, histologically. No other treatment-related changes were noted. The 450 ppm dose was a clear no-effect level (approximately 73 mg DIMP/kg body wt/day). Compared to reports of similar studies of DIMP in rats and dogs, these mink displayed no unique species susceptibility.
Subject(s)
Mink/physiology , Organophosphorus Compounds/toxicity , Animal Feed , Animals , Blood Cell Count/drug effects , Body Weight/drug effects , Cholinesterases/blood , Eating/drug effects , Erythrocyte Count/drug effects , Female , Heinz Bodies/drug effects , Hematocrit , Hematopoiesis/drug effects , Hemoglobins/metabolism , Male , Reticulocyte Count/drug effects , Spleen/cytology , Spleen/drug effectsABSTRACT
The in vivo metabolism of N,N'-dimethoxymethyl phenobarbital (DMMP) and the anticonvulsant properties of its metabolites were studied in the rat. At 10 and 30 minutes after i.p. administration, DMMP (ethyl-1-14C) represented less than 3% of plasma radioactivity, whereas N-monomethoxymethyl phenobarbital (MMP) was 78 and 75%, respectively, phenobarbital (PB) 12 and 20%, apparent mephobarbital 6 and 2% and less than 5% of the radioactivity remained at the origin. Peak levels of MMP were reached at 30 minutes in liver and 60 minutes in plasma and brain. At 4 hours, MMP had declined to 7% in plasma and was not detected in brain while PB rose to 93% of total 14C in plasma and brain. SKF-525A blocked (90%) the in vivo conversion of DMMP to MMP and completely inhibited the formation of PB, apparent mephobarbital and unidentified polar metabolites. MMP after oral administration was effective against maximum electroshock seizures at a time when brain levels of PB derived from MMP were insufficient to account for the total observed protection. However, MMP appears less potent than PB against pentylenetetrazol seizures.
Subject(s)
Anticonvulsants/metabolism , Phenobarbital/analogs & derivatives , Animals , Anticonvulsants/therapeutic use , Brain/metabolism , Chromatography, Thin Layer , Electroshock , Liver/metabolism , Male , Pentylenetetrazole , Phenobarbital/metabolism , Phenobarbital/therapeutic use , Rats , Seizures/chemically induced , Seizures/prevention & control , Time FactorsABSTRACT
Two clinical investigations of a new anticonvulsant, eterobarb, N,N' dimethoxymethyl phenobarbital (DMMP), were conducted in separate geographic regions. The drug has considerable efficacy in reducing the frequency of partial seizures, with and without secondary generalization, as well as generalized tonic-clonic seizures. Sedation did not appear to be as prominent with this barbiturate as it was with phenobarbital or primidone.
