Carrillo J A, Herraiz A G, Ramos S I, Benítez J
Department of Pharmacology and Psychiatry, Medical School, University of Extremadura, Badajoz, Spain.
J Clin Psychopharmacol. 1998 Aug;18(4):311-6. doi: 10.1097/00004714-199808000-00011.
Both clozapine (CLZ) and caffeine are CYP1A2 substrates. This study raises the hypothesis of whether caffeine withdrawal from the diet alters the metabolism and/or clinical status of patients receiving CLZ. Seven schizophrenic patients (six men and one woman) receiving monotherapy with CLZ at 271+/-102 mg/day (3.73+/-1.4 mg/kg) participated in the study. CLZ, norclozapine (NOR), and clozapine-N-oxide (NOX) were assayed in plasma by high-performance liquid chromatography at three different time points: A, with concomitant intake of caffeine from the diet; B, after caffeine withdrawal for 5 days; and C, after 2 weeks of rechallenge to habitual caffeine intake. The CYP1A2 activity was determined by means of a urinary caffeine test. After a caffeine-free diet for 5 days, CLZ concentrations relative to time point A decreased from 486 to 306 ng/mL (-47%) (p < 0.02), NOX levels decreased from 66 to 49 ng/mL (-31%) (p < 0.03), and the NOR/CLZ ratio significantly increased from 0.47 to 1.04 (185%) (p < 0.02). All parameters returned to initial figures at time point C. The NOR/CLZ ratio was significantly correlated to the CYP1A2 index (rs = 0.96, p < 0.0005). In conclusion, changes in the habitual caffeine intake alter the metabolism of CLZ in schizophrenic patients. Thus, patient intake of caffeine should be medically supervised, and the monitoring of CLZ and metabolite levels may be warranted. Furthermore, in those patients who receive therapy with CLZ, the NOR/CLZ ratio may provide an additional and valuable estimate of CYP1A2 activity.
氯氮平（CLZ）和咖啡因均为细胞色素P450 1A2（CYP1A2）的底物。本研究提出了一个假设，即饮食中停止摄入咖啡因是否会改变接受CLZ治疗患者的代谢和/或临床状态。7例接受CLZ单药治疗的精神分裂症患者（6例男性，1例女性）参与了本研究，CLZ剂量为271±102 mg/天（3.73±1.4 mg/kg）。在三个不同时间点采用高效液相色谱法测定血浆中的CLZ、去甲氯氮平（NOR）和氯氮平氮氧化物（NOX）：A点，同时从饮食中摄入咖啡因；B点，停止摄入咖啡因5天后；C点，重新摄入习惯剂量的咖啡因2周后。通过尿咖啡因试验测定CYP1A2活性。在无咖啡因饮食5天后，相对于A时间点，CLZ浓度从486 ng/mL降至306 ng/mL（-47%）（p<0.02），NOX水平从66 ng/mL降至49 ng/mL（-31%）（p<0.03），NOR/CLZ比值从0.47显著增加至1.04（185%）（p<0.02）。所有参数在C时间点恢复到初始数值。NOR/CLZ比值与CYP1A2指数显著相关（rs = 0.96，p<0.0005）。总之，习惯摄入咖啡因的改变会影响精神分裂症患者CLZ的代谢。因此，患者咖啡因的摄入应接受医学监督，可能需要监测CLZ及其代谢物水平。此外，对于接受CLZ治疗的患者，NOR/CLZ比值可能为CYP1A2活性提供额外且有价值的评估。
