Therapeutic Drug Monitoring and Clinical Outcomes in Epileptic Egyptian Patients: A Gene Polymorphism Perspective Study

Abstract

This work was performed to explore the effect of polymorphism in multidrug resistant genes on plasma phenytoin levels and patient outcome to evaluate its involvement in drug resistance and toxicity, which is usually associated with antiepileptic drugs. Therefore, we genotyped the adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1) 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 3 and 6 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 subjects (P < 0.0001). The C polymorphism was over-represented among patients with drug-resistant epilepsy as compared with either those with drug-responsive epilepsy (P < 0.001) or control subjects (P < 0.001). 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 of patients who had their plasma phenytoin levels at 20 microg/mL or less. Responsive patients showed no deviation from the control group regarding the genotype (P > 0.05) or allele frequency (P > 0.05). In conclusion, because most of the antiepileptic drugs are multidrug resistant gene substrates, the ABCB1 is thus an important candidate gene for 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.

Genetic Association Analysis of ATP Binding Cassette Protein Family Reveals a Novel Association of ABCB1 Genetic Variants with Epilepsy Risk, but Not with Drug-Resistance

“…Ethno-geographical differences in allele frequency distribution was also reflected in the haplotype distributions of these three loci, where it was found to be differing in AED resistant and responsive epilepsy cohort among different ethnicities studied (Table S4 in File S1) . This increased levels of diversity between populations could be indicative of positive selection, resulting in the allele frequency changes in the population under selection pressure, which may be mediated by distinct environmental or cultural influences as has been suggested earlier [ 46 ], [ 47 ].…”

Homeostatic bioenergetic network regulation: a novel concept to avoid pharmacoresistance in epilepsy

“…Those studies need to be treated with caution, however, because data are derived from patients that have been treated with AEDs for many years [41]. Attention has focused on polymorphisms in the gene encoding P-glycoprotein, MDR1, and a C/T polymorphism at base 3435 has been associated with resistance to phenytoin and pentobarbital, both drugs transported by human P-glycoprotein [42, 43]. Importantly, a CC genotype was associated with lower phenobarbital levels in CSF than the CT or TT genotype at position 3435 [43].…”

Polymorphism of ABCB1/MDR1 C3435T in Children and Adolescents with Partial Epilepsy is due to Different Criteria for Drug Resistance – Preliminary Results

“…These findings have stimulated scientists to further study the MDR1 gene polymorphism. The confirmation of Siddiqui’s findings was obtained in non-Caucasian patients, which may indicate that racial factors play a role [25,27,48]. …”