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 1;102(15):5507-12. Epub 2005 Apr 1.

Department of Biology, University College London, Darwin Building, Gower Street, London WC1E 6BT, United Kingdom.

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.

Download full-text PDF

Source Listing
April 2005
10 Reads

Article Mentions

Provided by Crossref Event Data

Publication Analysis

Top Keywords

carbamazepine phenytoin
anti-epileptic drugs
maximum doses
phenytoin carbamazepine
281 patients
patients report
cohorts 425
425 281
set stage
stage prospective
report functional
associated maximum
maximum dose
dose phenytoin
phenytoin 00066
highly associated
cyp2c9 highly

Altmetric Statistics


(Supplied by CrossRef)
Article in European journal of clinical pharmacology
K  pfer et al.
European journal of clinical pharmacology 1984
Article in Pediatric neurology
Ceulemans et al.
Pediatric neurology 2004
Article in Genome Research
Genome Research 2004
Article in New England Journal of Medicine
Siddiqui et al.
New England Journal of Medicine 2003
Article in The pharmacogenomics journal
Kerb et al.
The pharmacogenomics journal 2001
Article in Journal of pharmacokinetics and biopharmaceutics
Wilkinson et al.
Journal of pharmacokinetics and biopharmaceutics 1996
Article in Pharmacogenetics
Ozdemir et al.
Pharmacogenetics 2000
Article in Drug Metabolism and Disposition
Hsieh et al.
Drug Metabolism and Disposition 2001
Article in Pharmacogenetics
Eiselt et al.
Pharmacogenetics 2001
Article in Advanced drug delivery reviews
Lamba et al.
Advanced drug delivery reviews 2002

Similar Publications