title: Quantification in patient urine samples of felbamate and three metabolites: acid carbamate and two mercapturic acids.
abstract: OBJECTIVE
  Previously we proposed and provided evidence for the metabolic pathway of felbamate (FBM), which leads to the reactive metabolite, 3-carbamoyl-2-phenylpropion-aldehyde. This aldehyde carbamate was suggested to be the reactive intermediate in the oxidation of 2-phenyl-1,3-propanediol monocarbamate to the major human metabolite 3-carbamoyl-2-phenylpropionic acid. In addition, the aldehyde carbamate was found to undergo spontaneous elimination to 2-phenylpropenal, commonly known as atropaldehyde. Moreover, atropaldehyde was proposed to play a role in the development of toxicity during FBM therapy. Evidence for atropaldehyde formation in vivo was reported with the identification of modified N-acetyl-cysteine conjugates of atropaldehyde in both human and rat urine after FBM administration. Identification of the atropaldehyde-derived mercapturic acids in urine after FBM administration is consistent with the hypothesis that atropaldehyde is formed in vivo and that it reacts with thiol nucleophiles. Based on the hypothesis that the potential for toxicity will correlate to the amount of atropaldehyde formed, we sought to develop an analytic method that would quantify the amount of relevant metabolites excreted in patient urine.
  
  
  METHODS
  We summarize the results of an LC/MS method used to quantify FBM, 3-carbamoyl-2-phenylpropionic acid and two atropaldehyde-derived mercapturic acids in the patient population.
  
  
  RESULTS
  Analysis was performed on 31 patients undergoing FBM therapy. The absolute quantities of FBM and three metabolites were measured.
  
  
  CONCLUSIONS
  This method demonstrated sufficient precision for the identification of patients exhibiting "abnormal" levels of atropaldehyde conjugates and may hold potential for patient monitoring.
authors.affiliation: Department of Chemistry, University of Virginia, Charlottesville, USA.
authors.forename: C D
authors.initials: CD
authors.lastname: Thompson
authors.forename: M T
authors.initials: MT
authors.lastname: Barthen
authors.forename: D W
authors.initials: DW
authors.lastname: Hopper
authors.forename: T A
authors.initials: TA
authors.lastname: Miller
authors.forename: M
authors.initials: M
authors.lastname: Quigg
authors.forename: C
authors.initials: C
authors.lastname: Hudspeth
authors.forename: G
authors.initials: G
authors.lastname: Montouris
authors.forename: L
authors.initials: L
authors.lastname: Marsh
authors.forename: J L
authors.initials: JL
authors.lastname: Perhach
authors.forename: R D
authors.initials: RD
authors.lastname: Sofia
authors.forename: T L
authors.initials: TL
authors.lastname: Macdonald
mesh_terms: D000111:Acetylcysteine / Q000652:urine*; D000447:Aldehydes / Q000652:urine*; D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism* / Q000652:urine*; D002219:Carbamates / Q000652:urine; D002851:Chromatography, High Pressure Liquid; D004827:Epilepsy / Q000188:drug therapy / Q000378:metabolism; D000078328:Felbamate; D006801:Humans; D013058:Mass Spectrometry; D048448:Phenylcarbamates; D011409:Propylene Glycols / Q000378:metabolism* / Q000652:urine*; D011865:Radioisotope Dilution Technique; D051381:Rats
chemical_list: D000447:Aldehydes; D000927:Anticonvulsants; D002219:Carbamates; D048448:Phenylcarbamates; D011409:Propylene Glycols; D000111:Acetylcysteine; D000078328:Felbamate