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Research ArticleArticle

Tissue Distribution, Metabolism, and Clearance of the Convulsant Trimethylolpropane Phosphate in Rats

John Rossi III, Anne E. Jung, Glenn D. Ritchie, James W. Lindsey and Alan F. Nordholm
Drug Metabolism and Disposition November 1998, 26 (11) 1058-1062;
John Rossi III
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Anne E. Jung
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Glenn D. Ritchie
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James W. Lindsey
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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

  • 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

  • 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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Drug Metabolism and Disposition
Vol. 26, Issue 11
1 Nov 1998
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Research ArticleArticle

Tissue Distribution, Metabolism, and Clearance of the Convulsant Trimethylolpropane Phosphate in Rats

John Rossi, Anne E. Jung, Glenn D. Ritchie, James W. Lindsey and Alan F. Nordholm
Drug Metabolism and Disposition November 1, 1998, 26 (11) 1058-1062;

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Research ArticleArticle

Tissue Distribution, Metabolism, and Clearance of the Convulsant Trimethylolpropane Phosphate in Rats

John Rossi, Anne E. Jung, Glenn D. Ritchie, James W. Lindsey and Alan F. Nordholm
Drug Metabolism and Disposition November 1, 1998, 26 (11) 1058-1062;
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