Valpromide (VPD)
and valnoctamide (VCD) are two isomers which are aliphatic amides derived from short fatty acids that possess anticonvulsant activity. Our previous studies with VPD, VCD, and other related compounds showed that the biotransformation of these amides to their respective homologous acids is the key issue in their possessing pharmacological activity. In this study, we explored the structure pharmacokinetic relationships of the following five isomers or analogues of VPD: diisproprylacetamide (DID), diallylacetamide (DAD), octanamide (OAD), ethylisobutylacetamide (EID), and dimethylbutylacetamide (DBD). In addition, the anticonvulsant activity of these compounds was evaluated and compared with that of VPD and VCD. No plasma levels of OAD could be detected after its iv administration. Octanamide (OAD) was very rapidly metabolized to its homologous acid, octanoic acid (OM). Octanamide (OAD) was different from the other four amides investigated, having a high clearance (due to metabolic processes in the blood) and possessing the least anticonvulsant activity. All of the other amides were stable in blood and showed similar pharmacokinetic parameters. Unlike the other amides, DID and VCD did not metabolize to their respective homologous acids due to the fact that they had a substituted p position in their aliphatic side chain. Our study showed that, despite similarities in the chemical structures of the amides investigated, significant differences were observed in their pharmacokinetics and in the fraction of the amide ( f , ) biotransformed to its homologous acid. These differences in f, values may, therefore, account for the observed differences in the respective pharmacological activities, in general, and in the extent of the anticonvulsant activity, in particular, of the amides. In this particular series of aliphatic amides, which were derived from short-branched fatty acids, the biotransformation of the amide to its homologous acid appeared dependent on the chemical structure, especially on the substitution at the p position of the molecule.
Valpromide (VPD), a primary amide of valproic acid, has been used in several European countries as an antiepileptic and antipsychotic agent.13 Valnoctamide (VCD), a n isomer o f VPD, has also been in use as an anxiolytic drug43 and it also possesses anticonvulsant activity.6 Previous reports by Pisani e t a1.3.7.8 and from our laboratory9 have shown that upon oral administration to humans, VPD i s a prodrug of valproic acid (VPA), a well-known antiepileptic agent.10 This fact may account for the antiepileptic activity of VPD. Following iv administration t o humans, VPD was shown to be rapidly and almost completely metabolized to VPA; w i t h an f, value of 80% ( f , = the fraction metabolized o f VPD to VPAI.11 In dogs, the biotransformation o f VPD to VPA was only partial and independent o f the route of administration, its f, being in the range of 30-40%.12J3 Loscher and Nau14 reported that among a series of VPA analogues tested in mice for anticonvulsant activity, VPD was found t o be the most potent; it was 2-5 times more potent than VPA. However, VPD also exerted a more significant sedative side effect. Recent articles have reported that VPD also possesses specific properties o f its own (unrelated to VPA); that is, the induction of an elevation in the plasma levels o f carbamazepine-l0,ll-epoxide, the active metabolite of carbamazepine.15-1s
In a recent study in dogs, we reported that the major pharmacokinetic parameters of VCD were similar to those o f VPD;20