Pharmacokinetics and pharmacodynamics of valproate analogues in rats. I. Spiro[4.6]undecane-2-carboxylic acid.
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 the standard anticonvulsant 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 or cosubstrate depletion. The volume of distribution of the spiro compound also evidenced nonlinearity, possibly due to concentration-dependent binding to serum proteins. In contrast, the dose-dependent clearance displayed by VPA was composed of both saturable and nonsaturable components. Furthermore, the disposition of VPA was characterized by a significant 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 mechanism of antiepileptic action and not due to the presence of active metabolites of the drug.
Liu
M J
MJ
Division of Pharmaceutics, School of Pharmacy, University of North Carolina, Chapel Hill 27599.
Scott
K R
KR
Pollack
G M
GM
D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013141:Spiro Compounds / Q000493:pharmacokinetics* / Q000494:pharmacology; D014635:Valproic Acid / Q000493:pharmacokinetics* / Q000494:pharmacology
D000927:Anticonvulsants; D013141:Spiro Compounds; C064944:ADD 93024; D014635:Valproic Acid