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首页> 外文期刊>The journal of clinical psychiatry >Repeated ingestion of grapefruit juice does not alter clozapine's steady-state plasma levels, effectiveness, and tolerability.
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Repeated ingestion of grapefruit juice does not alter clozapine's steady-state plasma levels, effectiveness, and tolerability.

机译：重复摄入葡萄柚汁不会改变氯氮平的稳态血浆水平，有效性和耐受性。

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BACKGROUND: Grapefruit juice can inhibit the gastrointestinal activity of cytochrome P450 (CYP) 3A4, while its effect on CYP1A2 remains controversial. Several grapefruit juice bioflavonoids also modulate the activity of the drug transporter P-glycoprotein in the gut and in the blood-brain barrier. Both CYP1A2 and CYP3A4 are involved in clozapine metabolism. This study investigated the effects of repeated ingestion of grapefruit juice on multiple-dose pharmacokinetics and pharmacodynamics of clozapine in schizophrenic patients. METHOD: Clozapine therapy was initiated for fifteen treatment-resistant schizophrenic inpatients (DSM-IV criteria). The doses were individually titrated from day -35 to day -15 and then kept unchanged from day -14 to day 49. Regular-strength grapefruit juice (250 mL) was coadministered b.i.d. with each clozapine dose from day 15 to day 28. Plasma levels of clozapine and its main metabolites (norclozapine and clozapine N-oxide) were obtained, and clinical efficacy and safety assessments were completed prior to juice administration (days 0, 7, and 14), during the coadministration (days 17, 21, and 28), and after cessation of the juice (days 35, 42, and 49). RESULTS: After reaching steady states, plasma concentrations of clozapine and its metabolites and Positive and Negative Syndrome Scale scores were not significantly altered by the effect of grapefruit juice ingestion. The Clinical Global Impressions scale scores, Calgary Depression Scale scores, and side effect profiles (by the Extrapyramidal Symptom Rating Scale, the UKU Side Effect Rating Scale, and thorough examinations including electrocardiography and electroencephalography) also remained constant during the study. CONCLUSION: Consumption of regular-strength grapefruit juice, 250 mL b.i.d., for 14 days did not significantly impact clozapine metabolism, clinical efficacy, or tolerability. One reason is that enzymes other than CYP3A4 also mediate clozapine disposition. Also, grapefruit juice inhibits CYP3A4 in the gut, but not in the liver. The preliminary results also suggest that clozapine is unlikely to be a P-glycoprotein substrate. Further rigorous studies are necessary to reconfirm these findings.
机译：背景：葡萄柚汁可抑制细胞色素P450（CYP）3A4的胃肠道活性，但其对CYP1A2的作用仍存在争议。几种葡萄柚汁中的生物类黄酮还可以调节肠道和血脑屏障中药物转运蛋白P-糖蛋白的活性。 CYP1A2和CYP3A4均参与氯氮平的代谢。这项研究调查了反复摄入​​柚子汁对精神分裂症患者氯氮平的多剂量药代动力学和药效学的影响。方法：氯氮平治疗针对15例治疗耐药的精神分裂症患者（DSM-IV标准）开始。从第-35天到第-15天分别滴定剂量，然后从第-14天到第49天保持不变。常规强度的葡萄柚汁（250mL）在b.i.d.中共施用。从第15天到第28天服用每一种氯氮平剂量。获得了氯氮平及其主要代谢物（去氯氮平和氯氮平N-氧化物）的血浆水平，并在给药果汁之前（第0、7和14天）完成了临床疗效和安全性评估），在共同服药期间（第17、21和28天）以及果汁停止服用后（第35、42和49天）。结果：葡萄柚汁摄入后，达到稳态后，氯氮平及其代谢产物的血浆浓度以及正负综合症量表得分均无明显变化。在研究过程中，临床总体印象量表评分，卡尔加里抑郁量表评分和副作用概况（通过锥体外系症状评分量表，UKU副作用评分量表以及包括心电图和脑电图在内的全面检查）也保持不变。结论：每天服用250毫升常规强度葡萄柚汁持续14天对氯氮平的代谢，临床疗效或耐受性没有明显影响。原因之一是除CYP3A4以外的其他酶也介导氯氮平的分布。此外，葡萄柚汁抑制肠道中的CYP3A4，但不抑制肝脏中的CYP3A4。初步结果还表明，氯氮平不太可能是P-糖蛋白的底物。为了确认这些发现，还需要进行更严格的研究。

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