Ferslew K E, Hagardorn A N, Harlan G C, McCormick W F
Department of Pharmacology, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, USA.
J Forensic Sci. 1998 Sep;43(5):1082-5.
A case is presented of a fatal drug interaction caused by ingestion of clozapine (Clozaril) and fluoxetine (Prozac). Clozapine is a tricyclic dibenzodiazepine derivative used as an "atypical antipsychotic" in the treatment of severe paranoid schizophrenia. Fluoxetine is a selective serotonin reuptake inhibitor used for the treatment of major depression. Clinical studies have proven that concomitant administration of fluoxetine and clozapine produces increased plasma concentrations of clozapine and enhances clozapine's pharmacological effects due to suspected inhibition of clozapine metabolism by fluoxetine. Blood, gastric, and urine specimens were analyzed for fluoxetine by gas chromatography/mass spectrometry (GC/MS) and for clozapine by gas-liquid chromatography (GLC). Clozapine concentrations were: plasma, 4.9 micrograms/mL; gastric contents, 265 mg; and urine, 51.5 micrograms/mL. Fluoxetine concentrations were: blood, 0.7 microgram/mL; gastric contents, 3.7 mg; and urine 1.6 micrograms/mL. Norfluoxetine concentrations were: blood, 0.6 microgram/mL, and none detected in the gastric contents or urine. Analysis of the biological specimens for other drugs revealed the presence of ethanol (blood, 35 mg/dL; vitreous, 56 mg/dL; and urine 153 mg/dL) and caffeine (present in all specimens). The combination of these drugs produced lethal concentrations of clozapine and high therapeutic to toxic concentrations of fluoxetine. The deceased had pulmonary edema, visceral vascular congestion, paralytic ileus, gastroenteritis and eosinophilia. These conditions are associated with clozapine toxicity. The combined central nervous system, respiratory and cardiovascular depression of these drugs was sufficient to cause death. The death was determined to be a clozapine overdose due to a fatal drug interaction.
本文报告了一例因同时服用氯氮平（Clozaril）和氟西汀（Prozac）导致的致命药物相互作用病例。氯氮平是一种三环二苯并二氮䓬衍生物，用作“非典型抗精神病药物”，用于治疗重度偏执型精神分裂症。氟西汀是一种选择性5-羟色胺再摄取抑制剂，用于治疗重度抑郁症。临床研究证明，同时服用氟西汀和氯氮平会使氯氮平的血浆浓度升高，并增强氯氮平的药理作用，推测这是由于氟西汀抑制了氯氮平的代谢。采用气相色谱/质谱联用（GC/MS）法分析血液、胃内容物和尿液标本中的氟西汀，采用气液色谱法（GLC）分析氯氮平。氯氮平浓度分别为：血浆4.9微克/毫升；胃内容物265毫克；尿液51.5微克/毫升。氟西汀浓度分别为：血液0.7微克/毫升；胃内容物3.7毫克；尿液1.6微克/毫升。去甲氟西汀浓度分别为：血液0.6微克/毫升，胃内容物和尿液中未检测到。对其他药物的生物标本分析显示存在乙醇（血液35毫克/分升；玻璃体液56毫克/分升；尿液153毫克/分升）和咖啡因（所有标本中均有）。这些药物的组合产生了致死浓度的氯氮平和高治疗浓度至中毒浓度的氟西汀。死者出现肺水肿、内脏血管充血、麻痹性肠梗阻、肠胃炎和嗜酸性粒细胞增多。这些情况与氯氮平毒性有关。这些药物对中枢神经系统、呼吸系统和心血管系统的联合抑制足以导致死亡。经判定，该死亡是由于致命的药物相互作用导致的氯氮平过量所致。
