The chemistry, toxicology, and identification in rat and human urine of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one: a reactive metabolite in felbamate bioactivation.
4-Hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one has been proposed to be a reactive metabolite of the anti-epileptic drug felbamate [Thompson et al. (1996) Chem. Res. Toxicol. 9, 1225-1229]. 4-Hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one exists in equilibrium with 3-oxo-2-phenylpropyl aminooate, which is known to eliminate to generate 2-phenylpropenal. Thus, this species is postulated to be a latent form of the ultimate reactive metabolite, 2-phenylpropenal. The chemistry of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one is proposed to parallel that of 4-hydroxycyclophosphamide, the bioactivated form of cyclophosphamide that undergoes ring-opening to aldophosphamide and subsequent elimination to afford 2-propenal (acrolein). The work presented here reports the chemical synthesis of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one and demonstrates that under buffered conditions it exists in equilibrium with 3-oxo-2-phenylpropyl aminooate. The rate-limiting step in the decomposition of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one is the irreversible beta-elimination from 3-oxo-2-phenylpropyl aminooate to 2-phenylpropenal. We have found the half-life of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one to be 4.6 +/- 0.4 h under in vitro conditions that mimic the physiological setting. As a consequence of the relatively long half-life of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one, we have sought evidence for the significance of this pathway in experimental and clinical conditions. We report here the observation of this metabolite in the urine of rats being treated with 3-hydroxy-2-phenylpropyl aminooate, the esterase-mediated metabolite of felbamate, and in the urine of patients undergoing felbamate therapy. In addition, we have shown that 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one is toxic to cultured cells in a time-dependent manner, most likely as a result of its decomposition to 2-phenylpropenal. Taken together, the data support the hypothesis that 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one represents a "time-release" form of 2-phenylpropenal capable of traveling to distal sites from its locus of bioactivation and thereby mediates felbamate associated toxicities.
Dieckhaus
C M
CM
Chemistry Department, University of Virginia, Charlottesville, VA 22901, USA.
Santos
W L
WL
Sofia
R D
RD
Macdonald
T L
TL
D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism* / Q000633:toxicity / Q000652:urine; D001372:Aza Compounds / Q000737:chemistry / Q000633:toxicity* / Q000652:urine; D018929:Cell Culture Techniques; D000078328:Felbamate; D006207:Half-Life; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007668:Kidney / Q000166:cytology; D010078:Oxazines; D048448:Phenylcarbamates; D011409:Propylene Glycols / Q000378:metabolism* / Q000633:toxicity / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley
C438109:4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one; D000927:Anticonvulsants; D001372:Aza Compounds; D010078:Oxazines; D048448:Phenylcarbamates; D011409:Propylene Glycols; D000078328:Felbamate