CICAB, Clinical Research Centre, Extremadura University Hospital and Medical School, Badajoz, Spain.
Pharmacogenomics J. 2013 Aug;13(4):359-61. doi: 10.1038/tpj.2012.19. Epub 2012 May 29.
Pharmacogenetic studies have shown that genetic defects in drug-metabolizing enzymes encoded by CYP2C9, CYP2C19 genes and by the transporter ABCB1 gene can influence phenytoin (PTH) plasma levels and toxicity. The patient reported here is a 2-year-old girl with a medical history of cryptogenic (probably symptomatic) epilepsy, who had her first focal seizure with secondary generalization at 13 months of age. She initially received oral valproate treatment and three months later, she was prescribed an oral oxcarbazepine treatment. At 20 months of age, she was admitted to the Emergency Department because of generalized convulsive Status Epilepticus needing to be immediately treated with rectal diazepam (0.5 mg kg(-1)), intravenous diazepam (0.3 mg kg(-1)), and intravenous phenytoin with an initial-loading dose of 15 mg kg(-1). However, two hours after the initial-loading dose of PTH, the patient developed dizziness, nystagmus, ataxia and excessive sedation. Other potential causes of PTH toxicity were excluded such as drug interactions, decreased albumin or lab error. Therefore, to explain the neurological toxicity, PTH plasma levels and CYP2C9, CYP2C19 and ABCB1 genetic polymorphisms were analyzed. Initial plasma PTH levels were higher than expected (69 mg l(-1); normal range: 10-20 mg l(-1)), and the patient was homozygous for the CYP2C92 allele, heterozygous for the CYP2C194 allele and homozygous for the 3435C and 1236C ABCB1 alleles. Present findings support the previously established relationship between CYP2C9 and CYP2C19 genetic polymorphisms and the increased risk to develop PTH toxicity owing to high plasma concentrations. Nevertheless, although the association of these genes with PTH-induced adverse effects has been well-documented in adult populations, this is the first report examining the influence of these genetic polymorphisms on PTH plasma levels and toxicity in a pediatric patient.
药物遗传学研究表明，细胞色素 P450（CYP）2C9、CYP2C19 基因编码的药物代谢酶和 ABCB1 基因的遗传缺陷可影响苯妥英（PTH）的血浆水平和毒性。本报告中患者为 2 岁女孩，有隐源性（可能为症状性）癫痫病史，于 13 个月龄时首次出现继发性全身发作的局灶性癫痫发作。初始接受口服丙戊酸钠治疗，3 个月后换用口服奥卡西平治疗。20 个月龄时，因全身强直阵挛性癫痫持续状态紧急入住急诊病房，给予直肠地西泮（0.5mg/kg）、静脉地西泮（0.3mg/kg）和初始负荷剂量 15mg/kg 的静脉苯妥英治疗。然而，初始负荷剂量 PTH 给药后 2 小时，患者出现头晕、眼球震颤、共济失调和过度镇静。排除了其他可能导致 PTH 毒性的原因，如药物相互作用、白蛋白降低或实验室错误。因此，为了解释神经毒性，分析了 PTH 血浆水平和 CYP2C9、CYP2C19 和 ABCB1 基因多态性。初始 PTH 血浆水平高于预期（69mg/L；正常范围：10-20mg/L），患者 CYP2C92 等位基因纯合，CYP2C194 等位基因杂合，ABCB1 基因 3435C 和 1236C 等位基因纯合。目前的发现支持 CYP2C9 和 CYP2C19 基因多态性与 PTH 毒性增加之间的先前建立的关系，这是由于高血浆浓度导致 PTH 毒性增加的风险。尽管这些基因与 PTH 诱导的不良反应之间的关联在成人人群中得到了很好的证实，但这是首次在儿科患者中研究这些基因多态性对 PTH 血浆水平和毒性的影响的报道。
