Quantification in Patient Urine Samples of Felbamate and Three Metabolites: Acid Carbamate and Two Mercapturic Acids

Abstract

Summary:Purpose: Previously we proposed and provided evidence for the metabolic pathway of felbamate (FBM), which leads to the reactive metabolite, 3-carbamoyl-2-phenylpropionaldehyde. 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 LClMS 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 3 I 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.

Quantifying the Metabolic Activation of Nevirapine in Patients by Integrated Applications of NMR and Mass Spectrometries

“…10). The only other examples of this type of analysis for human pharmaceuticals are those of paracetamol, phenacetin, felbamate, and valproic acid, where the drug mercapturates were identified and quantified (Siegers et al, 1984;Veronese et al, 1985;Thompson et al, 1999;Dieckhaus et al, 2002;Gopaul et al, 2003). However, this is only the second minimum estimate in humans of bioactivation of an idiosyncratically toxic drug that is still used widely.…”

“…Metabolic activation of felbamate, an antiepileptic drug associated with idiosyncratic aplastic anemia and hepatotoxicity, can also be assessed in patients by monitoring (two) urinary mercapturates (Dieckhaus et al, 2002). In fact, the urinary metabolite ratio (mercapturate/felbamate ϫ 100) for the major mercapturate (4.5-27; mean, 14.7) is appreciably higher than it is for NVP-M2 (Thompson et al, 1999). However, the candidate population for felbamate is now highly restricted.…”

Therapeutic Drug Monitoring of the Newer Anti-Epilepsy Medications

“…In terms of pharmacokinetics, felbamate has high bioavailability (>90%). Approximately 50% of the parent drug is ultimately metabolized by the liver to inactive metabolites [54]. It is suspected that one or more of the metabolites mediates the rare but serious adverse effects [55].…”

Therapeutic Drug Monitoring of Antiepileptic Medications

“…It is suspected that one or more metabolites of felbamate mediate the rare but serious adverse effects (Shumaker et al, 1990). Approximately 50% of the parent drug is metabolized by the liver to inactive metabolites (Shumaker et al, 1990;Thompson et al, 1999). Inducers of hepatic metabolism increase the metabolism of felbamate Wagner et al, 1991), while valproic acid inhibits the metabolism (Ward et al, 1991).…”