Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin

• DOI: 10.1073/pnas.0407346102
• Publication Date: 2005-04-02T01:26:24Z
• Authors: Sarah K. Tate; Chantal Depondt; Sanjay M. Sisodiya; Gianpiero L. Cava...; Stephanie Schorge; Nicole Soranzo; Maria Thom; Arjune Sen; Simon D. Shorvon; Josemir W. Sander; Nicholas W. Wood; David B. Goldstein
• Keywords: Male; Adult; Genetic Markers; Adolescent; Genotype; Molecular Sequence Data; Nerve Tissue Proteins -- genetics; Cohort Studies; Neurologie; Brain -- metabolism; Humans; Exons -- genetics; Amino Acid Sequence; Aryl Hydrocarbon Hydroxylases -- genetics; Carbamazepine -- administration & dosage -- therapeutic use; Phenytoin -- administration & dosage -- therapeutic use; Polymorphism; Preschool; Child; Alleles; Aged; Cytochrome P-450 CYP2C9; Anticonvulsants -- administration & dosage -- therapeutic use; Sodium Channels -- genetics; Epilepsy; Base Sequence; Introns -- genetics; Infant; Brain; Exons; Genetic Markers -- genetics; Middle Aged; 3. Good health; Carbamazepine; Child, Preschool; Anticonvulsants; Female; Genetic -- genetics; Aryl Hydrocarbon Hydroxylases; Epilepsy -- drug therapy

Phenytoin and carbamazepine are effective and inexpensive anti-epileptic drugs (AEDs). As with many AEDs, a broad range of doses is used, with the final “maintenance” dose normally determined by trial and error. Although many genes could influence response to these medicines, there are obvious candidates. Both drugs target the α-subunit of the sodium channel, encoded by theSCNfamily of genes. Phenytoin is principally metabolized by CYP2C9, and both are probable substrates of the drug transporter P-glycoprotein. We therefore assessed whether variation in these genes associates with the clinical use of carbamazepine and phenytoin in cohorts of 425 and 281 patients, respectively. We report that a known functional polymorphism inCYP2C9is highly associated with the maximum dose of phenytoin (P= 0.0066). We also show that an intronic polymorphism in theSCN1Agene shows significant association with maximum doses in regular usage of both carbamazepine and phenytoin (P= 0.0051 andP= 0.014, respectively). This polymorphism disrupts the consensus sequence of the 5′ splice donor site of a highly conserved alternative exon (5N), and it significantly affects the proportions of the alternative transcripts in individuals with a history of epilepsy. These results provide evidence of a drug target polymorphism associated with the clinical use of AEDs and set the stage for a prospective evaluation of how pharmacogenetic diagnostics can be used to improve dosing decisions in the use of phenytoin and carbamazepine. Although the case made here is compelling, our results cannot be considered definitive or ready for clinical application until they are confirmed by independent replication.