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

Proceedings of the National Academy of Sciences of the United States of America - Tập 102 Số 15 - Trang 5507-5512 - 2005
Sarah K. Tate1, Chantal Depondt1, Sanjay M. Sisodiya1, Gianpiero L. Cavalleri1, Stéphanie Schorge1, Nicole Soranzo1, Maria Thom1, Arjune Sen1, Simon Shorvon1, Josemir W. Sander1, Nicholas Wood1, David B. Goldstein1
1Department of Biology, University College London, Darwin Building, Gower Street, London WC1E 6BT, United Kingdom; Departments of Clinical and Experimental Epilepsy and Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, United Kingdom; National Society for Epilepsy, Chalfont-Saint-Peter, Bucks SL9 0RJ, United Kingdom; and Institute for Genome Sciences and Policy, Center for Population Genomics and Pharmacogenetics, Duke University, 101 Science...

Tóm tắt

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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Proceedings of the National Academy of Sciences of the United States of America

Tập 102 Số 15

5507-5512

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