Journal
PHARMACOGENOMICS
Volume 14, Issue 1, Pages 35-45Publisher
FUTURE MEDICINE LTD
DOI: 10.2217/PGS.12.180
Keywords
ABCB1; ABCC2; carbamazepine; CYP3A4; EPHX1; pharmacogenomics; pharmacokinetics; UGT2B7
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Funding
- NIH/National Institute of Neurological Disorder and Stroke [P50 NS16308, K01NS050309]
- Lundbeck Inc.
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Aim: The aim of this study was to evaluate the association of genetic variants in the major genes involved in carbamazepine (CBZ) metabolism and transport with its pharmacokinetics in epilepsy patients. Materials & methods: Twenty-five SNPs within seven CBZ pathway genes, namely CYP3A4, CYP3A5, EPHX1, NR1I2, UGT2B7, ABCB1 and ABCC2, were analyzed for association with CBZ pharmacokinetics in 90 epilepsy patients. Results: The CYP3A4*1B SNP was significantly associated with CBZ clearance. Significant association of EPHX1 SNPs was observed with greater carbamazepine-10,11-trans dihydrodiol: carbamazepine 10-11 epoxide ratios. Among drug transporters, ABCB1 and ABCC2 SNPs were significantly associated with altered CBZ clearance. Conclusion: SNPs within CBZ pathway genes contribute to interpatient variation in CBZ pharmacokinetics and might contribute to pharmacoresistant epilepsy. Although our results need further clinical validation in a larger patient cohort, they indicate that genetic variation in CBZ pathway genes could influence its pharmacokinetics, and hence would have clinical significance. Original submitted 2 August 2012; Revision submitted 16 October 2012
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