Association of polymorphisms in EPHX1, UGT2B7, ABCB1, ABCC2, SCN1A and SCN2A genes with carbamazepine therapy optimization

Author:

Hung Chin-Chuan12,Chang Wei-Lun1,Ho Jia-Ling1,Tai John Jen3,Hsieh Tsung-Jen3,Huang Hsiao-Ching1,Hsieh Yow-Wen12,Liou Horng-Huei4

Affiliation:

1. Department of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan

2. Department of Pharmacy, China Medical University Hospital, Taichung, Taiwan

3. Division of Biostatistics, College of Public Health, National Taiwan University, Taiwan

4. Department of Neurology & Pharmacology, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan.

Abstract

Aim: Carbamazepine (CBZ) is one of the most widely used antiepileptic drugs. The aim of the present study is to investigate the impacts of polymorphisms in genes related to pharmacokinetic and pharmacodynamic pathways of CBZ on the large interindividual variability in dosages and concentrations. Methods & results: Genetic polymorphisms in the candidate genes were detected in 234 epileptic patients under maintenance CBZ monotherapy by real-time PCR and PCR-RFLP. Results of statistical analysis demonstrated that carriers of the variant SCN1A IVS5–91G>A and EPHX1 c.337T>C allele tended to require higher CBZ dosages and lower ln(concentration–dose ratios) than noncarriers (p < 0.0001) and the homozygous carriers also seemed to require higher CBZ dosages and lower ln(concentration–dose ratios) (p < 0.0001). In addition, the multiple regression model of concentration–dose ratio of CBZ also revealed that genetic variants in SCN1A, EPHX1 and UGT2B7 genes interactively affect the concentration–dose ratio of CBZ (adjusted r2 = 55%). Conclusion: The present study identified genetic factors associated with CBZ therapy optimization and provided useful information for individualized CBZ therapy in epileptic patients. Further studies in larger populations are needed to confirm our results. Original submitted: 22 July 2011; Revision submitted: 27 September 2011

Publisher

Future Medicine Ltd

Subject

Pharmacology,Genetics,Molecular Medicine

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