Potentially reactive cyclic carbamate metabolite of the antiepileptic drug felbamate produced by human liver tissue in vitro.
Felbamate (FBM) is a novel antiepileptic drug that was approved in 1993 for treatment of several forms of epilepsy. After its introduction, toxic reactions (aplastic anemia and hepatotoxicity) associated with its use were reported. It is unknown whether FBM or one of its metabolites is responsible for these idiosyncratic adverse reactions. Although the metabolism of FBM has not been fully characterized, three primary metabolites of FBM have been identified, i.e. 2-hydroxy, p-hydroxy, and monocarbamate metabolites. In addition, the monocarbamate metabolite leads to a carboxylic acid, which is the major metabolite of FBM in humans. Formation of the hydroxylated products of FBM involves cytochrome P450 enzymes, but the enzymes involved in the formation and further metabolism of the monocarbamate have not yet been elucidated. Recently, mercapturate metabolites of FBM have been identified in human urine, and a metabolic scheme involving reactive aldehyde metabolite formation from the monocarbamate metabolite has been proposed. The present study confirmed the formation of the proposed metabolites using human liver tissue in vitro. The aldehyde intermediates were trapped as oxime derivatives, and the cyclic equilibrium product (proposed as a storage and transport form for the aldehydes) was monitored directly by HPLC or GC/MS. Formation of putative toxic aldehyde intermediates and the major carboxylic acid metabolite of FBM was differentially effected with the cofactors NADP+ and NAD+. It is possible that the cofactors may influence the relative metabolism via activation and inactivation pathways.
Kapetanovic
I M
IM
Epilepsy Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Torchin
C D
CD
Thompson
C D
CD
Miller
T A
TA
McNeilly
P J
PJ
Macdonald
T L
TL
Kupferberg
H J
HJ
Perhach
J L
JL
Sofia
R D
RD
Strong
J M
JM
D000927:Anticonvulsants / Q000493:pharmacokinetics*; D001711:Biotransformation; D002219:Carbamates / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000078328:Felbamate; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D048448:Phenylcarbamates; D011409:Propylene Glycols / Q000493:pharmacokinetics*; D018629:Spectrometry, Mass, Secondary Ion
D000927:Anticonvulsants; D002219:Carbamates; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D048448:Phenylcarbamates; D011409:Propylene Glycols; D009243:NAD; D009249:NADP; D000078328:Felbamate