Murphy Andrea, Wilbur Kerry
School of Nursing, Dalhousie University, Halifax, Nova Scotia, Canada.
Ann Pharmacother. 2003 May;37(5):659-63. doi: 10.1345/aph.1C413.
To report a case of phenytoin toxicity potentially associated with concurrent diazepam therapy.
A 44-year-old First Nations man presented to the emergency department with headache, nystagmus, diplopia, and ataxia. Apart from a long-standing seizure disorder, his past medical history was unremarkable. The antiepileptic drug regimen of phenytoin, phenobarbital, and lamotrigine had been unchanged for almost 5 months. Total phenytoin serum concentration reported 2 weeks prior to hospital admission was 8 micro g/L. Two days prior to admission, he was prescribed amoxicillin and diazepam; he denied use of nonprescription or herbal medications. The serum phenytoin concentration drawn in the hospital was 37 micro g/mL. Both phenytoin and diazepam were stopped, and the symptoms resolved. His neurologic abnormalities were attributed to phenytoin toxicity caused by an interaction with diazepam.
The literature documenting a potential interaction between diazepam and phenytoin is conflicting. Case reports and controlled studies have demonstrated both increases and decreases in serum phenytoin concentrations when these agents were administered concomitantly. Phenytoin induces the metabolism of drugs that are substrates of CYP2C, CYP2D, and CYP3A; however, phenytoin is eliminated predominantly by CYP2C9- and CYP2C19-dependent hepatic metabolism. Diazepam is one example of a drug that is extensively metabolized by CYP2C19 and could potentially influence phenytoin elimination by acting as an alternate substrate for this isoenzyme. In our patient, the timing of drug administration, clinical and physical examination findings, and laboratory data suggest that diazepam therapy resulted in phenytoin toxicity. Use of the Naranjo probability scale indicated a probable relationship between the adverse clinical effects observed and phenytoin and diazepam coadministration in this patient.
Phenytoin is a known inducer of drugs metabolized by CYP2C, CYP2D, and CYP3A, but its own metabolism may be altered by drugs influencing CYP2C9 or CYP2C19, such as diazepam. Agents not acting as enzyme inhibitors or inducers, but instead behaving as alternate substrates for enzyme-binding sites, may produce clinically relevant drug interactions through an underrecognized mechanism.
报告一例可能与同时使用地西泮治疗相关的苯妥英中毒病例。
一名44岁的原住民男性因头痛、眼球震颤、复视和共济失调就诊于急诊科。除了长期的癫痫发作障碍外，他既往的病史并无异常。苯妥英、苯巴比妥和拉莫三嗪的抗癫痫药物治疗方案近5个月未变。入院前2周报告的苯妥英血清总浓度为8μg/L。入院前两天，他被开了阿莫西林和地西泮；他否认使用非处方药或草药。入院时检测的血清苯妥英浓度为37μg/mL。苯妥英和地西泮均停药，症状缓解。他的神经功能异常归因于与地西泮相互作用导致的苯妥英中毒。
关于地西泮与苯妥英之间潜在相互作用的文献存在矛盾。病例报告和对照研究表明，当同时使用这些药物时，血清苯妥英浓度既有升高也有降低。苯妥英诱导CYP2C、CYP2D和CYP3A底物药物的代谢；然而，苯妥英主要通过依赖CYP2C9和CYP2C19的肝脏代谢消除。地西泮是一种被CYP2C19广泛代谢的药物，可能通过作为该同工酶的替代底物而潜在地影响苯妥英的消除。在我们的患者中，给药时间、临床和体格检查结果以及实验室数据表明地西泮治疗导致了苯妥英中毒。使用Naranjo概率量表表明，观察到的不良临床效应与该患者同时使用苯妥英和地西泮之间可能存在关联。
苯妥英是已知的CYP2C、CYP2D和CYP3A代谢药物的诱导剂，但其自身的代谢可能会被影响CYP2C9或CYP2C19的药物改变，如地西泮。那些不作为酶抑制剂或诱导剂，而是作为酶结合位点替代底物的药物，可能通过一种未被充分认识的机制产生临床相关的药物相互作用。
