There is very little SAR among the clinically useful anticon-vulsants except within each structure type, primarily effecting their side effects and toxicities. Thus, these aspects of medicinal chemistry will be covered under each structure type or under the individual drug monographs covered in this section.
Valproic Acid (Depakote, Depakene, Depacon)
VPA is an established AED with a simple chemical structure but an unusually broad spectrum of action. It is generally well tolerated, but its use is limited by two rare but significant toxic side effects (hepatotoxicity and teratogenicity) that can be dose-dependent or idiosyncratic in nature.9,39,40 These drawbacks are apparently shared by its equipotent active metabolite, (E)-2-propyl-2-pentenoic acid (2-ene-VPA) (Fig. 14.3).
VPA is also an important inhibitor of the cytochrome P450 isozymes, mainly of CYP2C9 and also of uridine diphosphate (UDP)-glucuronyl transferase and epoxide hydrolase.10 This inhibition is competitive and dose-dependent, and its effect is observed when sufficient concentrations of VPA is achieved (usually within 24 hours). Thus, an increase in the plasma concentrations of other AEDs such as lamotrigine is to be expected after dosing with VPA.
Metabolism of VPA is very complex and is the result of hepatic mitochondrial 3-oxidation and microsomal oxidations, catalyzed by CYP2C9, CYP2C19, and CYP2E1 and possibly CYP3A4, and glucuronidations.39,40 At least 10 metabolites have been identified. The major urinary inactive metabolite is 2-propyl-3-keto-pentanoic acid (3-keto-VPA) and an equipotent active metabolite, (E)-2-ene-VPA. Other minor metabolites identified are their hydroxylated or dehydrated products, and 2-propylglutaric acid (see Fig.14.3 for their structures). All of these metabolites are excreted as O-glucuronides.
The hepatotoxicity of VPA is most likely associated with 2, 4-diene-VPA and/or 4-epoxy-VPA rather than the 4-ene-VPA originally suggested because its closely related
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