Impact of gene polymorphism on therapeutic drug monitoring of phenytoin and outcome in epileptic patients

ABSTRACT

This work was performed to explore the effect of polymorphism in multidrug resistant gene [MDR1] on plasma phenytoin levels and patients' outcome to evaluate its involvement in drug resistance and toxicity that is usually associated with antiepileptic drugs. Therefore, we genotyped the MDR1 in 100 patients, suffering from partial or generalized tonic-clonic seizures and receiving phenytoin, and 50 healthy control subjects. Steady state plasma phenytoin levels were also determined in the epileptic patients. Patients were evaluated after three and six months and were classified either as drug resistant patients or responsive patients. Results revealed 37 patients with drug-responsive epilepsy and 63 patients with drug-resistant epilepsy. Genotyping of our patients and control subjects revealed a genotype distribution of [CC, CT, TT 55.50%, 38.00%, 6.50%] for drug resistant patients, [CC, CT, TT 13.50%, 46.00%, 40.50%] for drug responsive patients, and [CC, CT, TT 24.00%, 48.00%, 28.00%] for the control subjects. Patients with drug-resistant epilepsy were more likely to have the CC than the TT genotype compared with either responsive patients [P< 0.0001] or control [P <0.0001]. The C polymorphism was overrepresented among patients with drug-resistant epilepsy as compared with either those with drug-responsive epilepsy [P <0.001] or control [P <0.001]. Out of the total 100 epileptic patients; 13 patients had their plasma phenytoin levels exceeding the maximum safe concentration. These 13 patients were more likely to have TT genotype than the CC genotype compared with the remainder patients who had their plasma phenytoin levels patients showed no deviation from the control group regarding the genotype [P >0.05] or allele frequency [P>0.05]. In Since most of the antiepileptic drugs are MDR1 substrates, thus the MDR1 is an important candidate gene potentially influencing the response to antiepileptic drugs. Our findings suggest that using genotype data may make it possible to safely reduce the time required to reach an effective dose. Therefore, it is a priority to assess the utility of dose adjustment on the basis of genotype for these medicines that are substrates for this gene