STEREOSELECTIVE PHARMACOKINETICS OF STIRIPENTOL - AN EXPLANATION FOR THE DEVELOPMENT OF TOLERANCE TO ANTICONVULSANT EFFECT

An earlier pharmacodynamic study of the chiral antiepileptic drug stir ipentol in an intravenous pentylenetetrazol-induced seizure model in t he rat showed the development of a significant degree of tolerance to the anticonvulsant and neurotoxic effects following subacute treatment with the racemic compound. A more recent study with the pure enantiom ers of stiripentol indicated that the (+)-enantiomer is 2.4 times more potent than the (-)-enantiomer, based on a comparison of brain EC(50) values for the anticonvulsant effect. Moreover, (-)-stiripentol has a much longer elimination half-life than (+)-stiripentol. We have re-an alyzed the brain and blood samples from the first pharmacodynamic stud y using a newly developed chiral HPLC assay to investigate whether the tolerance phenomenon with racemic stiripentol was due to a shift in t he enantiomeric composition of stiripentol in brain tissue during repe titive administration of racemic drug. A large increase, as much as 5- 6-fold, in the (-)/(+) ratio in brain concentration of stiripentol was observed after subacute administration, as compared with that after a single dose of the racemic drug. The enrichment in the less potent en antiomers during repetitive drug administration explains the previous observation of an apparent development of tolerance when the pharmacol ogic effects were related to total [(-)+(+)] brain concentrations of s tiripentol as measured by a non-stereoselective assay. The results of this study highlight the importance of stereoselective pharmacokinetic s in investigating the pharmacodynamics of the racemic mixture of a ch iral anticonvulsant.