Brandolese R, Scordo M G, Spina E, Gusella M, Padrini R
Rehabilitation Service, Conselve Hospital, ULSS 17, 35131 Padua, Italy.
Clin Pharmacol Ther. 2001 Oct;70(4):391-4.
A 31-year-old woman who had a severe head injury was treated with oral phenytoin (100 mg 3 times a day) to prevent posttraumatic seizures. On day 10 of phenytoin treatment, 3 hours after the morning dose, the patient manifested neurologic signs compatible with phenytoin intoxication. Thus drug serum concentrations were monitored daily for 12 days. The elimination half-life was 103 hours, namely, about 5 times longer than the mean value generally quoted (22 hours). In the absence of any acquired predisposing factor for phenytoin toxicity, genetic mutations in the cytochrome P450 (CYP) enzymes responsible for phenytoin metabolism (CYP2C9 and CYP2C19) were suspected. Genotyping revealed that the patient was homozygous for the CYP2C93 allele (CYP2C93/3) and heterozygous for the CYP2C192 allele (CYP2C191/2). In view of the markedly reduced metabolic activity of CYP2C3 in comparison with the wild-type enzyme (about one fifth) and of the minor role of CYP2C19 in phenytoin metabolism, it is likely that CYP2C93 mutation was largely responsible for drug overdose.
一名31岁的严重头部受伤女性接受口服苯妥英钠（每日3次，每次100毫克）治疗以预防创伤后癫痫发作。在苯妥英钠治疗的第10天，晨服药物3小时后，患者出现了与苯妥英钠中毒相符的神经体征。因此，连续12天每天监测药物血清浓度。消除半衰期为103小时，即比通常引用的平均值（22小时）长约5倍。在没有任何获得性苯妥英钠毒性易感因素的情况下，怀疑负责苯妥英钠代谢的细胞色素P450（CYP）酶（CYP2C9和CYP2C19）发生了基因突变。基因分型显示，该患者为CYP2C93等位基因纯合子（CYP2C93/3），CYP2C192等位基因杂合子（CYP2C191/2）。鉴于与野生型酶相比，CYP2C3的代谢活性显著降低（约为五分之一），且CYP2C19在苯妥英钠代谢中的作用较小，很可能是CYP2C93突变在很大程度上导致了药物过量。
