Lucas R A, Gilfillan D J, Bergstrom R F
Eli Lilly and Company Limited, Lilly Research Centre, Windlesham, Surrey, UK.
Eur J Clin Pharmacol. 1998 Oct;54(8):639-43. doi: 10.1007/s002280050527.
Olanzapine is a novel antipsychotic, which is effective against both the positive and negative symptoms of schizophrenia and causes fewer extrapyramidal adverse effects than conventional antipsychotics. The purpose of the present study was to assess the potential for a pharmacokinetic interaction between olanzapine and carbamazepine, since these agents are likely to be used concomitantly in the treatment of manic psychotic disorder.
The pharmacokinetics of two single therapeutic doses of olanzapine were determined in 11 healthy volunteers. The first dose of olanzapine (10 mg) was taken alone and the second dose (10 mg) after 2 weeks of treatment with carbamazepine (200 mg BID). Measurement of urinary 6beta-hydroxycortisol/cortisol excretion was used as an endogenous marker to confirm that induction of CYP3A4 by carbamazepine had occurred.
The dose of olanzapine given after a 2-week pretreatment with carbamazepine was cleared more rapidly than olanzapine given alone. Olanzapine pharmacokinetic values for Cmax and AUC were significantly lower after the second dose, the elimination half-life was significantly shorter, and the clearance and volume of distribution were significantly increased.
Carbamazepine has been shown to induce several P450 cytochromes including CYP3A4 and CYP1A2. Since CYP1A2 plays a role in the metabolic clearance of olanzapine, the interaction may be attributed to induction of CYP1A2 by carbamazepine, leading to increased first-pass and systemic metabolism of olanzapine. The interaction is not considered to be of clinical significance because olanzapine has a wide therapeutic index, and the changes in plasma concentration of olanzapine are within the fourfold variation that occurs without concern for safety in a patient population.
奥氮平是一种新型抗精神病药物，对精神分裂症的阳性和阴性症状均有效，且与传统抗精神病药物相比，锥体外系不良反应较少。本研究的目的是评估奥氮平与卡马西平之间药代动力学相互作用的可能性，因为这两种药物可能会在治疗躁狂性精神病障碍时联合使用。
在11名健康志愿者中测定了两个单治疗剂量奥氮平的药代动力学。第一剂奥氮平（10毫克）单独服用，第二剂（10毫克）在服用卡马西平（200毫克，每日两次）2周后服用。尿中6β-羟基皮质醇/皮质醇排泄量的测定用作内源性标志物，以确认卡马西平已诱导CYP3A4。
在接受卡马西平预处理2周后给予的奥氮平剂量比单独给予的奥氮平清除更快。第二剂后奥氮平的Cmax和AUC药代动力学值显著降低，消除半衰期显著缩短，清除率和分布容积显著增加。
已证明卡马西平可诱导包括CYP3A4和CYP1A2在内的多种细胞色素P450。由于CYP1A2在奥氮平的代谢清除中起作用，这种相互作用可能归因于卡马西平对CYP1A2的诱导，导致奥氮平的首过代谢和全身代谢增加。这种相互作用不被认为具有临床意义，因为奥氮平具有较宽的治疗指数，且奥氮平血浆浓度的变化在患者群体中安全无忧的四倍变化范围内。
