Genetic variants in microsomal epoxide hydrolase influence carbamazepine dosing

Mohd Makmor Bakry, Graeme J. Sills, Nikolas Hitiris, Elaine Butler, Elaine A. Wilson, Martin J. Brodie

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Objectives:: 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 = 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.

Original languageEnglish
Pages (from-to)205-212
Number of pages8
JournalClinical Neuropharmacology
Volume32
Issue number4
DOIs
Publication statusPublished - Jul 2009
Externally publishedYes

Fingerprint

Epoxide Hydrolases
Carbamazepine
Genes
Epilepsy
Seizures
Pharmacokinetics
Genotype
Demography
Glycosyltransferases
Uridine Diphosphate
Sodium Channels
Cytochromes
Restriction Fragment Length Polymorphisms
Pharmaceutical Preparations
Anticonvulsants
Multivariate Analysis
Regression Analysis
Polymerase Chain Reaction
Enzymes

Keywords

  • Antiepileptic drugs
  • Carbamazepine
  • Cytochrome P450
  • Microsomal epoxide hydrolase
  • Pharmacogenetics

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Clinical Neurology

Cite this

Genetic variants in microsomal epoxide hydrolase influence carbamazepine dosing. / Makmor Bakry, Mohd; Sills, Graeme J.; Hitiris, Nikolas; Butler, Elaine; Wilson, Elaine A.; Brodie, Martin J.

In: Clinical Neuropharmacology, Vol. 32, No. 4, 07.2009, p. 205-212.

Research output: Contribution to journalArticle

Makmor Bakry, Mohd ; Sills, Graeme J. ; Hitiris, Nikolas ; Butler, Elaine ; Wilson, Elaine A. ; Brodie, Martin J. / Genetic variants in microsomal epoxide hydrolase influence carbamazepine dosing. In: Clinical Neuropharmacology. 2009 ; Vol. 32, No. 4. pp. 205-212.
@article{122aa051d03e437eb653aa6a1be40484,
title = "Genetic variants in microsomal epoxide hydrolase influence carbamazepine dosing",
abstract = "Objectives:: 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 = 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.",
keywords = "Antiepileptic drugs, Carbamazepine, Cytochrome P450, Microsomal epoxide hydrolase, Pharmacogenetics",
author = "{Makmor Bakry}, Mohd and Sills, {Graeme J.} and Nikolas Hitiris and Elaine Butler and Wilson, {Elaine A.} and Brodie, {Martin J.}",
year = "2009",
month = "7",
doi = "10.1097/WNF.0b013e318187972a",
language = "English",
volume = "32",
pages = "205--212",
journal = "Clinical Neuropharmacology",
issn = "0362-5664",
publisher = "Lippincott Williams and Wilkins",
number = "4",

}

TY - JOUR

T1 - Genetic variants in microsomal epoxide hydrolase influence carbamazepine dosing

AU - Makmor Bakry, Mohd

AU - Sills, Graeme J.

AU - Hitiris, Nikolas

AU - Butler, Elaine

AU - Wilson, Elaine A.

AU - Brodie, Martin J.

PY - 2009/7

Y1 - 2009/7

N2 - Objectives:: 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 = 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.

AB - Objectives:: 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 = 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.

KW - Antiepileptic drugs

KW - Carbamazepine

KW - Cytochrome P450

KW - Microsomal epoxide hydrolase

KW - Pharmacogenetics

UR - http://www.scopus.com/inward/record.url?scp=68949167778&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=68949167778&partnerID=8YFLogxK

U2 - 10.1097/WNF.0b013e318187972a

DO - 10.1097/WNF.0b013e318187972a

M3 - Article

VL - 32

SP - 205

EP - 212

JO - Clinical Neuropharmacology

JF - Clinical Neuropharmacology

SN - 0362-5664

IS - 4

ER -