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

Article Details

Citation

Tate SK, Depondt C, Sisodiya SM, Cavalleri GL, Schorge S, Soranzo N, Thom M, Sen A, Shorvon SD, Sander JW, Wood NW, Goldstein DB

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

Proc Natl Acad Sci U S A. 2005 Apr 12;102(15):5507-12. Epub 2005 Apr 1.

PubMed ID
15805193 [ View in PubMed
]
Abstract

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 alpha-subunit of the sodium channel, encoded by the SCN family 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 in CYP2C9 is highly associated with the maximum dose of phenytoin (P = 0.0066). We also show that an intronic polymorphism in the SCN1A gene shows significant association with maximum doses in regular usage of both carbamazepine and phenytoin (P = 0.0051 and P = 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.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
PhenytoinSodium channel protein type 1 subunit alphaProteinHumans
Yes
Inhibitor
Details
PhenytoinSodium channel protein type 2 subunit alphaProteinHumans
Yes
Inhibitor
Details
PhenytoinSodium channel protein type 3 subunit alphaProteinHumans
Unknown
Not AvailableDetails
PhenytoinSodium channel protein type 8 subunit alphaProteinHumans
Yes
Inhibitor
Details
Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
PhenytoinCytochrome P450 2C9ProteinHumans
No
Substrate
Inhibitor
Inducer
Details
Pharmaco-genomics
DrugInteracting Gene/EnzymeAllele nameGenotypesDefining change(s)Type(s)DescriptionDetails
PhenytoinCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*3(A;C) / (C;C)Effect Directly StudiedPatients with this genotype have reduced metabolism of phenytoin.Details