Genetic variants in microsomal epoxide hydrolase influence carbamazepine dosing.
OBJECTIVE
The dose of carbamazepine required to achieve optimal seizure control varies widely from patient to patient. We investigated polymorphic variants in various genes involved in the pharmacokinetics and pharmacodynamics of carbamazepine in an effort to identify predictors of maintenance dose.


METHODS
: A total of 70 patients with epilepsy (49% were males; median age, 34 years; range, 14-72 years) who had benefited (>50% reduction in seizure frequency for at least 12 months) from treatment with carbamazepine monotherapy were included in the analysis. Known variants in drug-metabolizing enzyme genes, including those encoding cytochrome P450s, uridine 5'-diphosphate-glycosyltransferase, and microsomal epoxide hydrolase, together with a sodium channel polymorphism in SCN2A, were screened using polymerase chain reaction-restriction fragment length polymorphism or direct sequencing. Associations between demographic and genetic variables and carbamazepine dose were identified by univariate and multivariate regression analyses.


RESULTS
All genotype frequencies were consistent with Hardy-Weinberg equilibrium (P > 0.05). No single demographic or genetic variable was of sufficient strength to independently influence carbamazepine dosing requirements. However, a multivariate model, incorporating patient age and specific genotypes (c.337T>C, c.416A>G) of the EPHX1 gene encoding microsomal epoxide hydrolase, revealed a significant association with the maintenance dose of carbamazepine (r(2) = 0.362, P= 0.002).


CONCLUSIONS
This proof-of-principle study suggests that genetic variants in EPHX1 can be used to predict maintenance doses of carbamazepine. A large-scale prospective investigation of genetic influences on drug dosing strategies in epilepsy, with specific focus on whole gene variability for those proteins involved in the pharmacokinetics and pharmacodynamics of antiepileptic agents, is warranted.
Makmor-Bakry
Mohd
M
Epilepsy Unit, Section of Clinical Pharmacology & Stroke Medicine, University Division of Cardiovascular & Medical Sciences, Western Infirmary, Glasgow, Scotland.
Sills
Graeme J
GJ
Hitiris
Nikolas
N
Butler
Elaine
E
Wilson
Elaine A
EA
Brodie
Martin J
MJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000927:Anticonvulsants / Q000009:adverse effects / Q000493:pharmacokinetics*; D002220:Carbamazepine / Q000009:adverse effects / Q000493:pharmacokinetics*; D004827:Epilepsy / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D004851:Epoxide Hydrolases / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D055815:Young Adult
D000927:Anticonvulsants; D002220:Carbamazepine; D004851:Epoxide Hydrolases