Genetic Predictors of the Maximum Doses Patients Receive during Clinical Use of the Anti-Epileptic Drugs Carbamazepine and Phenytoin
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 obv...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 102; no. 15; pp. 5507 - 5512 |
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Main Authors | , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
National Academy of Sciences
12.04.2005
National Acad Sciences |
Subjects | |
Online Access | Get full text |
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Summary: | 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 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. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 To whom correspondence should be addressed. E-mail: d.goldstein@duke.edu. This paper was submitted directly (Track II) to the PNAS office. Author contributions: S.K.T., C.D., S.M.S., S.S., S.D.S., J.W.S., N.W.W., and D.B.G. designed research; S.K.T., C.D., S.M.S., G.L.C., S.S., N.S., S.D.S., J.W.S., and N.W.W. performed research; S.K.T., C.D., S.S., and N.S. analyzed data; M.T. and A.S. contributed new reagents/analytic tools; and S.K.T., C.D., S.M.S., S.S., N.W.W., and D.B.G. wrote the paper. Abbreviations: AED, anti-epileptic drug; ADR, adverse drug reaction; tSNP, tagging SNP. S.K.T. and C.D. contributed equally to this work. Edited by Arno G. Motulsky, University of Washington School of Medicine, Seattle, WA, and approved February 15, 2005 |
ISSN: | 0027-8424 1091-6490 |
DOI: | 10.1073/pnas.0407346102 |