Pharmacokinetics and Pharmacodynamics of Valproate Analogues in Rats. I. Spiro[4.6]Undecane-2-Carboxylic Acid

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Abstract
The pharmacokinetic and pharmacodynamic properties of the spiro carboxylic acid, spiro [4.6]undecane-2-carboxylic acid (SUCA, ADD 93024), were investigated in rats and compared with those of standard anticovulsant carboxylic acid, valproate (VPA). The clearance of SUCA was dose-dependent, although the observed nonlinearity did not appear to be due to classical saturable elimination. The change in clearance across doses was consistent with end-product inhibition of cosubstrate depletion. The volume of distribution of the spiro compound also evidenced nonlinearity, possibly due to concentration-dependent binding to serum proteins. In conrast, the dose-dependent clearance displayed by VPA was composed of both saturable and non-saturable components. Furthermore, the disposition of VPA was characterized by a sufficient enterohepatic recirculation, whereas no such recirculatory process was apparent for SUCA. Both compounds afforded significant protection from pentylenetetrazol (PTZ)-induced seizures, and the time course of anticonvulsant effect did not correspond to that of drug concentrations in serum for either anticonvulsant. The apparent dissociation between the pharmacokinetics and pharmacodynamics of VPA may be a function of the mechanis mf antiepileptic action and not due to the presence of active metabolites of the drug.

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