Despite considerable progress in the pharmacotherapy of epilepsy, more than 30% of patients are reported to be resistant to antiepileptic drugs. Multidrug resistance 1 (MDR1) gene could play a role in drug resistance in epilepsy. In this study, the authors investigated the association between the MDR1 gene polymorphisms, C3435T and G2677AT, and drug resistance epilepsy by using polymerase chain reaction/restriction fragment length polymorphism and pyrosequencing methods in a group of 39 patients with drug-resistant epilepsy and 92 controls. No associations were found between the polymorphisms of the MDR1 gene and drug-resistant epilepsy. Haplotype analysis showed no significant association. Compound genotype analysis showed that CC3435/GG2677 was significantly higher in the control group compared to the patient group. In conclusion, MDR1 polymorphisms investigated in this study are not associated with antiepileptic drug resistance, but the CC3435/GG2677 compound genotype might have an effect on antiepileptic drug response.
Regesta G., Tanganelli P.Clinical aspects and biological bases of drug-resistant epilepsies. Epilepsy Res. 1999;34:109-122.
2.
Kwan P., Brodie MJPotential role of drug transporters in the pathogenesis of medically intractable epilepsy. Epilepsia. 2005; 46:224-235.
3.
Juliano RL, Ling V.A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta. 1976;455:152-162.
4.
Chin JE, Soffir R., Noonan KE, et al. Structure and expression of the human MDR1 (P-gp) gene family . Mol Cell Biol. 1989;9: 3808-3820.
5.
Tischler DM, Weinberg KI, Hinton DR, et al. MDR1 gene expression in brain of patients with medically intractable epilepsy. Epilepsia. 1995;36:1-6.
6.
Löscher W., Potschka H.Role of multidrug transporters in pharmacoresistance to antiepileptic drugs. J Pharmacol Exp Ther. 2002;301:7-14.
7.
Ishikawa T., Hirano H., Onishi Y., et al. Functional evaluation of ABCB1 (P-glycoprotein) polymorhisms: high speed screening and structure-activity relationship analysis. Drug Metab Pharmacokinet. 2004;19:1-14.
8.
Hoffmeyer S. , Burk O., von Richter O., et al. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA. 2000;97:3473-3478.
9.
Siddiqui A., Kerb R., Weale ME, et al. Association of multidrug resistance in epilepsy with a polymorphism in the drug-transporter gene ABCB1. N Engl J Med. 2003;348:1442-1448.
10.
Tan NC, Heron SE, Scheffer IE, et al. Failure to confirm association of a polymorphism in ABCB1 with multidrug-resistant epilepsy. Neurology. 2004 ;63:1090-1092.
11.
Sills GJ, Mohanraj R., Butler E., et al. Lack of association between C3435T polymorphism in the human multidrug resistance (MDR1) gene and response to antiepileptic drug treatment . Epilepsia. 2005;46:643-647.
12.
Vahab SA, Sen S., Ravindran N., et al. Analysis of genotype and haplotype effects of ABCB1 (MDR1) polymorphisms in the risk of medically refractory epilepsy in an Indian population. Drug Metab Pharmacokinet. 2009;24:255-260.
13.
Chen L., Liu CQ, Hu Y., et al. Association of a polymorphism in MDR1 C3435T with response to antiepileptic drug treatment in ethic Han Chinese children with epilepsy. Zhongguo Dang Dai Er Ke Za Zhi. 2007;9:11-14.
14.
Sisodiya SM , Heffernan J., Squier MVOverexpression of Pglycoprotein in malformations of cortical development. Neuroreport. 1999 ;10:3437-3441.
15.
Kwan P., Baum L., Wong V., et al. Association between ABCB1 C3435T polymorphism and drug-resistant epilepsy in Han Chinese. Epilepsy Behav. 2007 ;11:112-117.
16.
Kim DW, Kim M., Lee SK, et al. Lack of association between C3435T nucleotide MDR1 genetic polymorphism and multidrug-resistant epilepsy. Seizure. 2006;15:344-347.
17.
Hung CC, Jen Tai J., Kao PJ, et al. Association of polymorphisms in NR1I2 and ABCB1 genes with epilepsy treatment responses. Pharmacogenomics. 2007 ;8:1151-1158.
18.
Kerb R., Aynacıoğlu AS, Brockmöller J., et al. The predictive value of MDR1, CYP2C9 and CYP2C19 polymorphisms for phenytoin plasma levels. Pharmacogenomics J. 2001;1:204-210.
19.
Holmes GLEpilepsy in the developing brain: lessons from the laboratory and clinic. Epilepsia. 1997;38:12-30.
20.
Kim RB, Leake BF, Choo EF, et al. Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther. 2001;70:189-199.
21.
Tanabe M., Ieiri I., Nagata N., et al. Expression of P-glycoprotein in human placenta: relation to genetic polymorphism of the multidrug resistance (MDR)-1 gene. J Pharmacol Exp Ther. 2001; 279:1137-1143.
Zimprich F. , Sunder-Plassmann R., Stogmann E., et al. Association of an ABCB1 gene haplotype with pharmacoresistance in temporal lobe epilepsy . Neurology. 2004;63:1087-1089.
24.
Horinouchi M., Sakeada T., Nakamura T., et al. Significant genetic linkage of MDR1 polymorphisms at positions 3435 and 2677: functional relevance to pharmacokinetics of digoxin. Pharm Res. 2002;19:1581-1585.
25.
Kurata Y., Ieiri I., Kimura M., et al. Role of human MDR1 gene polymorhism in bioavailibility and interaction of digoxin, a substrate of P-glycoprotein. Clin Pharmacol Ther. 2002;72: 209-219.
