atropaldehyde (reactive metabolite)
4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one atropaldehyde (reactive metabolite)
Figure 14.10 • Metabolic biotransformation of felbamate.
phenylpropanal (atropaldehyde) that is normally deactivated as a cysteine conjugate via the GSH/glutathione transferase pathway discussed earlier under the metabolism of VPA.39 Isolation of 4-hydroxy-5-phenyl-1, 3-oxazaper-hydroin-2-one (i.e., a precursor for 2-phenylpropionalde-hyde in human urine) provided further evidence linking this toxic metabolite to the observed clinical toxicities.53 Similar to VPA discussed earlier, placement of a fluorine atom at the C-2 position of FBM resulted in a very potent anticonvulsant, 2-fluorofelbamate that lacks the idiosyncratic properties of FBM. Fluorofelbamate is currently under phase II clinical trials.54
It should be pointed out that although FBM has no effect on CYP2C9, it is an inhibitor of CYP2C19 and also inhibits the mitochondrial enzymes responsible for ^-oxidation. Thus, drug interactions between FBM and VPA are to be expected.55
Chemical structures of these newer broad-spectrum anticonvulsants are shown in Figure 14.11. All of these drugs have unique mechanisms of action and will be discussed in individual drug monographs.
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