Stereoselective pharmacokinetics of stiripentol: an explanation for the development of tolerance to anticonvulsant effect.

An earlier pharmacodynamic study of the chiral antiepileptic drug stiripentol in an intravenous pentylenetetrazol-induced seizure model in the 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 enantiomers of stiripentol indicated that the (+)-enantiomer is 2.4 times more potent than the (-)-enantiomer, based on a comparison of brain EC50 values for the anticonvulsant effect. Moreover, (-)-stiripentol has a much longer elimination half-life than (+)-stiripentol. We have re-analyzed the brain and blood samples from the first pharmacodynamic study using a newly developed chiral HPLC assay to investigate whether the tolerance phenomenon with racemic stiripentol was due to a shift in the enantiomeric composition of stiripentol in brain tissue during repetitive 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 enantiomers during repetitive drug administration explains the previous observation of an apparent development of tolerance when the pharmacologic effects were related to total [(-)+(+)] brain concentrations of stiripentol as measured by a non-stereoselective assay. The results of this study highlight the importance of stereoselective pharmacokinetics in investigating the pharmacodynamics of the racemic mixture of a chiral anticonvulsant.