Abstract
In an attempt to understand the species-selective toxicity of felbamate (2-phenyl-1,3-propanediol dicarbamate, FBM), which is thought to result from bioactivation to 2-phenylpropenal, FBM metabolism was evaluated in rats and humans. The formation of 2-phenylpropenal was monitored by the amount of its mercapturates excreted in urine. The data show a relative 5-fold increase in mercapturate excretion in patient urine as a result of differences in metabolism through P450-, esterase-, and aldehyde dehydrogenase-mediated pathways. To compensate for the significant species differences in FBM metabolism, and to produce toxic levels of 2-phenylpropenal in rat comparable to humans levels, monocarbamate felbamate (2-phenyl-1,3-propanediol monocarbamate, MCF), was administered to rats in the hopes of eliciting a toxic response. The desired result, an increase in mercapturate excretion, was not observed in MCF-treated rats due to the identification of a new FBM metabolite, 2-phenyl-1,3-propanediol monocarbamate-α-d-glucuronic acid (MCF-glucuronide). Formation of MCF-glucuronide is significant and represents about 80% of MCF metabolites in MCF-dosed rats, 3% of FBM metabolites in FBM-dosed rats, and about 11% of FBM metabolites in FBM patients. To overcome the protective effect of glucuronidation, uridine diphosphoglucuronosyltransferase (UGT)-deficient Gunn rats were treated with FBM and MCF, which surprisingly had no effect on the amount of MCF-glucuronide formed. Given the known UGT polymorphisms and the fact that MCF glucuronidation contributes to the elimination of a 2-phenylpropenal precursor, the correlation between poor UGT activity and an increase in mercapturates excretion was evaluated in patients. The result of the first 34 patients screened suggests that a patient with poor UGT activity is not necessarily at risk for FBM toxicity.
Footnotes
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Send reprint requests to: Timothy L. Macdonald, Ph.D., University of Virginia, Department of Chemistry, McCormick Road, Charlottesville, VA 22901. E-mail: tlm{at}virginia.edu
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↵1 Presented in part at the 29th Annual Gordon Research Conference on Drug Metabolism, Plymouth, New Hampshire, July 4–8, 1999.
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This work was supported by Carter-Wallace, Inc. and National Institutes of Health Cell and Molecular Pharmacology Training Grant T32GM07055 (C.M.D.).
- Abbreviations used are::
- FBM
- felbamate (2-phenyl-1,3-propanediol dicarbamate)
- MCF
- monocarbamate felbamate (2-phenyl-1,3-propanediol monocarbamate)
- MCF-glucuronide
- 2-phenyl-1,3-propanediol monocarbamate-α-d-glucuronic acid
- d4-MCF-glucuronide
- 6-[3-(Aminocarbonyloxy)-2-phenyl-1,1,3,3-tetradeuteriopropoxy]-3,4,5-trihydroxyperhydro-2H-pyran-2-carboxylic acid
- UGT
- uridine diphosphoglucuronosyltransferase
- LC/ESI-MS
- liquid chromatography/electrospray ionization-mass spectrometry
- LC/ESI-MS/MS
- liquid chromatography/electrospray ionization-tandem mass spectrometry
- BSO
- buthionine-[S,R]-sulfoximine
- CPPA
- 3-carbamoyl-2-phenylpropionic acid
- RT
- retention time
- Received December 21, 1999.
- Accepted April 13, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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