A common polymorphism in the SCN1A gene associates with phenytoin serum levels at maintenance dose.
OBJECTIVE
A broad range of phenytoin doses is used in clinical practice, with the final 'maintenance' dose normally determined by trial and error. A common functional polymorphism in the SCN1A gene (one of the genes encoding the drug target) has been previously associated with maximum dose of phenytoin used clinically, and also maximum dose of carbamazepine, another antiepileptic drug with the same drug target.


METHODS
We have related variation at the SCN1A IVS5-91 G>A polymorphism to maximum dose and to maintenance dose of phenytoin in 168 patients with epilepsy treated with phenytoin. We also related genotype to phenytoin serum levels at maximum dose and at maintenance dose of phenytoin. We genotyped the polymorphism using an Applied Biosystems Taqman assay.


RESULTS
The polymorphism is associated with phenytoin serum concentration at maintenance dose (P=0.03). In a reduced cohort of 71 patients receiving phenytoin monotherapy this association is also significant (P=0.03). Neither association remains significant after Bonferroni correction for multiple testing.


CONCLUSIONS
These results are not a replication of the original study. They do, however, support the hypothesis that this polymorphism influences the clinical use of phenytoin. They also demonstrate the utility of using multiple phenotypes in pharmacogenetics studies, particularly when attempting to separate pharmacokinetic and pharmacodynamic effects. As the SCN1A polymorphism affects phenytoin pharmacodynamics, it is particularly useful to obtain data on serum levels in addition to dose because association of a pharmacodynamic variant may be stronger with serum levels than dose as the serum level may eliminate or reduce pharmacokinetic variability.
Tate
Sarah K
SK
Department of Biology, University College London, London, UK.
Singh
Rinki
R
Hung
Chin-Chuan
CC
Tai
John Jen
JJ
Depondt
Chantal
C
Cavalleri
Gianpiero L
GL
Sisodiya
Sanjay M
SM
Goldstein
David B
DB
Liou
Horng-Huei
HH
D000927:Anticonvulsants / Q000097:blood*; D001483:Base Sequence; D017931:DNA Primers; D005260:Female; D006801:Humans; D008297:Male; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010672:Phenytoin / Q000097:blood*; D011110:Polymorphism, Genetic; D015222:Sodium Channels / Q000235:genetics*
D000927:Anticonvulsants; D017931:DNA Primers; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568242:SCN1A protein, human; D015222:Sodium Channels; D010672:Phenytoin