Ebid Abdel-Hameed I Mohammed, Ahmed Mona M M, Mohammed Samah A
Department of Pharmacy Practice, Faculty of Pharmacy, Helwan University, Cairo, Egypt.
Ther Drug Monit. 2007 Jun;29(3):305-12. doi: 10.1097/FTD.0b013e318067ce90.
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.
开展这项研究是为了探究多药耐药基因多态性对苯妥英血浆水平及患者预后的影响，以评估其在耐药性和毒性（通常与抗癫痫药物相关）中的作用。因此，我们对100例患有部分性或全身性强直阵挛性发作且正在接受苯妥英治疗的患者以及50名健康对照者的三磷酸腺苷结合盒亚家族B成员1（ABCB1）进行了基因分型。同时也测定了癫痫患者的苯妥英稳态血浆水平。在3个月和6个月后对患者进行评估，并将其分为耐药患者或敏感患者。结果显示有37例药物敏感型癫痫患者和63例药物耐药型癫痫患者。对我们的患者和对照者进行基因分型发现，耐药患者的CC、CT、TT基因型分布为：55.50%、38.00%、6.50%；药物敏感患者的CC、CT、TT基因型分布为：13.50%、46.00%、40.50%；对照者的CC、CT、TT基因型分布为：24.00%、48.00%、28.00%。与敏感患者（P < 0.0001）或对照者（P < 0.0001）相比，耐药型癫痫患者更有可能具有CC基因型而非TT基因型。与药物敏感型癫痫患者（P < 0.001）或对照者（P < 0.001）相比，C多态性在耐药型癫痫患者中过度表达。在总共100例癫痫患者中，有13例患者的苯妥英血浆水平超过最大安全浓度。与其余血浆苯妥英水平在20μg/mL或更低的患者相比，这13例患者更有可能具有TT基因型而非CC基因型。敏感患者在基因型（P > 0.05）或等位基因频率（P > 0.05）方面与对照组无差异。总之，由于大多数抗癫痫药物都是多药耐药基因的底物，因此ABCB1是潜在影响抗癫痫药物反应的重要候选基因。我们的研究结果表明，利用基因型数据可能能够安全地缩短达到有效剂量所需的时间。因此，对于这些作为该基因底物的药物，优先评估基于基因型进行剂量调整的效用。
