Spaans E, van den Heuvel M W, Schnabel P G, Peeters P A M, Chin-Kon-Sung U G, Colbers E P H, Sitsen J M A
NV Organon, Clinical Pharmacology Department, PO Box 20, 5340 BH Oss, The Netherlands.
Eur J Clin Pharmacol. 2002 Sep;58(6):423-9. doi: 10.1007/s00228-002-0498-6. Epub 2002 Aug 14.
The objectives of this study were to assess the effect of mirtazapine on steady-state pharmacokinetics of phenytoin and vice versa and to assess tolerability and safety of the combined use of mirtazapine and phenytoin.
This was an open-label, randomised, parallel-groups, single-centre, multiple-dose pharmacokinetic study. Seventeen healthy, male subjects completed either treatment A [nine subjects: daily 200 mg phenytoin for 17 days plus mirtazapine (15 mg for 2 days continuing with 30 mg for 5 days) from day 11 to day 17] or treatment B [eight subjects: mirtazapine, daily 15 mg for 2 days continuing with 30 mg for 15 days plus phenytoin 200 mg from day 8 to day 17]. Serial blood samples were taken for kinetic profiling on the 10th and 17th days of treatment A and on the 7th and 17th days of treatment B. Induction of CYP 3A by phenytoin was evaluated by measuring the ratio of 6 beta-hydroxycortisol over cortisol on the 1st, 7th and 17th days of treatment B.
Co-administration of mirtazapine had no effect on the steady-state pharmacokinetics of phenytoin, i.e. the area under the plasma concentration-time curve (AUC)(0-24) and peak plasma concentration (C(max)) remained unchanged. The addition of phenytoin to an existing daily administration of mirtazapine resulted in a mean (+/-SD) decrease of the AUC(0-24) from 576+/-104 ng h/ml to 305+/-81.6 ng h/ml and a mean decrease of C(max) from 69.7+/-17.5 ng/ml to 46.9+/-10.9 ng/ml. Induction of CYP 3A by phenytoin is confirmed by the significantly ( P=0.001) increased 6beta-hydroxycortisol/cortisol ratio from 1.74+/-1.00 to 2.74+/-1.64.
Co-administration of mirtazapine did not alter the steady-state pharmacokinetics of phenytoin. The addition of phenytoin to an existing daily administration of mirtazapine results in a decrease of the plasma concentrations of mirtazapine by 46% on average, most likely due to induction of CYP 3A3/4.
本研究的目的是评估米氮平对苯妥英稳态药代动力学的影响以及反之情况，同时评估米氮平和苯妥英联合使用的耐受性和安全性。
这是一项开放标签、随机、平行组、单中心、多剂量药代动力学研究。17名健康男性受试者完成了治疗A组（9名受试者：第1天至第17天每日服用200mg苯妥英，共17天，从第11天至第17天加用米氮平，第1天至第2天每日15mg，之后第3天至第5天每日30mg）或治疗B组（8名受试者：第1天至第15天每日服用15mg米氮平，之后第8天至第17天加用200mg苯妥英）。在治疗A组的第10天和第17天以及治疗B组的第7天和第17天采集系列血样进行动力学分析。通过在治疗B组的第1天、第7天和第17天测量6β-羟基皮质醇与皮质醇的比值来评估苯妥英对CYP 3A的诱导作用。
米氮平与苯妥英联合使用时，对苯妥英的稳态药代动力学没有影响，即血浆浓度-时间曲线下面积（AUC）（0 - 24）和血浆峰浓度（C(max)）保持不变。在已有的每日米氮平给药基础上加用苯妥英，导致AUC（0 - 24）平均（±标准差）从576±104 ng·h/ml降至305±81.6 ng·h/ml，C(max)平均从69.7±17.5 ng/ml降至46.9±10.9 ng/ml。苯妥英对CYP 3A有诱导作用，这通过6β-羟基皮质醇/皮质醇比值从1.74±1.00显著（P = 0.001）增加到2.74±1.64得到证实。
米氮平与苯妥英联合使用未改变苯妥英的稳态药代动力学。在已有的每日米氮平给药基础上加用苯妥英，导致米氮平血浆浓度平均降低46%，最可能是由于CYP 3A3/4的诱导作用。
