Research Article

Association of carbamazepine major metabolism and transport pathway gene polymorphisms and pharmacokinetics in patients with epilepsy

Department of Experimental & Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA

^‡Authors contributed equally

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Angela K Birnbaum^‡

Department of Experimental & Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA

Center for Clinical & Cognitive Neuropharmacology, University of Minnesota, Minneapolis, MN, USA

^‡Authors contributed equally

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Susan E Marino^‡

Department of Experimental & Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA

Center for Clinical & Cognitive Neuropharmacology, University of Minnesota, Minneapolis, MN, USA

^‡Authors contributed equally

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Ghada Ahmed

Department of Experimental & Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA

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James C Cloyd

Department of Experimental & Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA

Center for Orphan Drug Research, University of Minnesota, Minneapolis MN, USA

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Rory P Remmel

Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA

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Ilo E Leppik

Department of Experimental & Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA

Department of Neurology, School of Medicine, University of Minnesota, Minneapolis, MN, USA

MINCEP Epilepsy Care, Minneapolis, MN, USA

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Jatinder K Lamba

* Author for correspondence

PUMA-Institute of Personalized Medicine, Minneapolis, MN, USA.

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Email the corresponding author at lamba004@umn.edu

Published Online:19 Dec 2012https://doi.org/10.2217/pgs.12.180

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Abstract

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

Keywords:

Papers of special note have been highlighted as: ▪▪ of considerable interest

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Published online 19 December 2012

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Acknowledgements

The authors would like to acknowledge W Oetting for assistance in DNA isolation, the BioMedical Genomics Center (BMGC) for genotyping facility and the Minnesota Supercomputing Institute at the University of Minnesota (MN, USA).

Financial & competing interests disclosure

This study was supported by NIH/National Institute of Neurological Disorder and Stroke grants P50 NS16308 (IE Leppik principal investigator and JC Cloyd coprincipal investigator) and K01NS050309 (SE Marino). AK Birnbaum, JC Cloyd and IE Leppik have a royalty agreement with Lundbeck Inc. related to the development of intravenous carbamazepine. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

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