16 - Genetic influences on responsiveness to anticonvulsant drugs

Summary

OVERVIEW

This chapter addresses pharmacogenetic issues associated with the clinical use of anticonvulsant drugs (ACDs). Individual variability in responsiveness has been documented for nearly all ACDs in common use and current perspectives suggest that genes play a significant causal role. Variation in the DNA sequence of genes that encode drug-metabolizing enzymes is a major factor contributing to differences in drug responsiveness, and several important polymorphisms have been documented to affect the disposition of ACDs, particularly, the influence of CYP2C9 and CYP2C19 on metabolism of phenytoin and mephenytoin, respectively. Although the metabolism of other ACDs may also involve polymorphisms producing CYP isoforms, additional studies are needed to determine if these polymorphisms affect pharmacokinetics. A much greater need, however, is for studies that focus on gene variations that encode target proteins against which ACDs act. Studies that relate genetic variation to ACD pharmacodynamics will provide insight into specific gene sequences and protein structures that are most important for drug action. Additionally, this experimental strategy will have the potential of identifying previously unknown drug targets and mechanisms of action. Together, information on genetic contribution to ACD pharmacokinetics and pharmacodynamics will enable more successful and less complicated use of this class of drugs.

Introduction

Clinical experience has documented that patients with epilepsy respond in different ways to standard ACDs. Individuals with similar seizure disorders based on diagnostic criteria exhibit variable responses to the same medication, with some patients deriving significant benefit and others none at all.