Associativity Of A Polymorphism In MDR1C3435T With Response To Antiepileptic Drugs Treatment In Intractable Epilepsy And The Pharmacological Mechanism Of The Levetiracetam

ObjectiveRecent evidences suggest that the homozygous C-variant,which is associated with higher expression and increased activity of P-gp,is more common in patients with refractory epilepsy.We have investigated the prevalence of this polymorphism in a series of patients in china.Levetiracetam was a new AED which was applied in the clinc.We have investigated levetiracetam as an additive therapy for refractory partial epilepsy and the mechanism about eluding P-glycoprotein which was encoded by multidrug resistance gene.MethodsWe divided Sixty four patients into two groups according to response to AEDs. The effective group had 31 patients,the ineffective group had 33 ones.The randomized,doubled-blind,placebo-controlled trials were carried out in 30 refractory subjects.All the 30 patients entered an 8-week baseline period followed by 4-week titration interval and a 12-week maintenance period.Levetiracetam were gived as an additive therapy.Patients initially received LEV 0.5g twice daily,2 weeks later changed to 1.0g twice daily,and after another 2 weeks increased to 1.5g twice daily. The main outcome was measured by the decrease of seizure frequency per week. DNA samples were obtained from the patients.Genetypes of the C3435T polymorphism were determined by traditional polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP).Results1.There were significant differences in the allele frequency(χ~2=20.17 P＜0.001 ) and genotype frequency(χ~2=16.13 P＜0.001 ) between the two groups. In nonresponders(n = 31),CC genotype frequencies were 20(64.5%),TT genotype frequencies were 9(29.0%),CT genotype frequencies were 2(6.5%) In responders(n = 33),6(18.2%) subjects were CC genotype,15(45.4%)subjects were TT genotype,12(36.4%) subjects were CT genotype.Comparison of responders and nonresponders,CC vs.TT,odds ratio 1.07,95%CI 1.47～21.10,P＜0.01, genetype CC vs.CT,odds ratio 20.00,95%CI 9.74～111.64,P＜0.005,there were significant differences. 2.In all 30 subjects,27 ones accomplished trials,LEV group had 18,the placebo had 9.In the CC genetype subjects,compared with placebo,LEV had the better therapeutic effect(Z_c = -2.013,P=0.042),6/9 of the subjects decreased the seizure frequency＞50%in the LEV group,in the placebo group 1/7 of ones did.In the LEV group,they were no significant differences between the CC genetype subjects and the CC and TT genetype ones(Zc =-0.144,P=0.888 ).Conclusions1.The patients with drug-resistent epilepsy were more likely to have the CC than the TT genotype,MDR1 might be taken as a relative risk factor.2.Levetiracetam had better therapeutic effect as an additive therapy for refractory epilepsy and significantly decreased the seizure frequency.3.There were multiple pharmacological mechanisms about LEV treatment refractory epilepsy,one of them might be that LEV was not the substrate for P-gp which was encoded by MDR1 gene.