Abstract
The distribution, metabolism, and clearance of trimethylolpropane phosphate (TMPP), a potent, bicyclophosphate, γ-aminobutyric acid-ergic convulsant, were studied in male Fischer-344 rats. Intraperitoneal administration of TMPP was compared with oral gavage with respect to rates of absorption, distribution, and clearance. Distribution of TMPP to major body tissues was evaluated for the first 24 hr after administration or, in the case of regional brain distribution, immediately after the first TMPP-induced clinical seizure. Samples purified from the urine, feces, and bile of rats exposed to TMPP, as well as from rat liver microsomes incubated with TMPP in vitro, were analyzed for possible phase I and phase II metabolism, using HPLC. The disposition and clearance of TMPP in the blood and major body tissues were measured. TMPP was found to be well distributed to highly vascularized tissue compartments, with little retention >24 hr after administration. TMPP was eliminated through the urine and feces as the parent compound, with no evidence of phase I or phase II metabolism. TMPP was rapidly cleared from the blood during the first 30 min after exposure, with slower clearance of >87% of the drug during the following 8-hr period and >99.5% clearance by 100 hr after injection. Repeated daily exposure to TMPP for up to 5 successive days resulted in no measurable accumulation in the brain or other major tissue compartments. Possible mechanisms for TMPP-induced, short- and long-term, neurobehavioral modulation are discussed.
Footnotes
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Send reprint requests to: Glenn D. Ritchie, Ph.D., NMRI/TD, 2612 Fifth Street, Building 433, WPAFB, OH 45433-7903. E-mail:gritchie{at}navy.al.wpafb.af.mil
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This research was funded by the Naval Medical Research and Development Command (Research Task 63706N.M0096.004–1516). The opinions and assertions contained herein are those of the authors and are not to be construed as official or reflecting the views of the Navy Department or the Naval Service at large. The experiments conducted herein were performed according to the principles set forth in the current (1996) edition of the Guide for the Care and Use of Laboratory Animals, Institute of Laboratory Animal Resources, National Research Council.
- Abbreviations used are::
- MIL-L-23699
- Military Specification L-23699 hydraulic fluid
- GABA
- γ-aminobutyric acid
- GTCS
- generalized tonic-clonic seizure(s)
- CNS
- central nervous system
- TMPP
- trimethylolpropane phosphate
- PIC
- picrotoxin
- PTZ
- pentylenetetrazol
- PE
- polyethylene
- Received March 13, 1998.
- Accepted June 2, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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