Jerling M, Lindström L, Bondesson U, Bertilsson L
Department of Clinical Pharmacology, Karolinska Institute, Huddinge Hospital, Sweden.
Ther Drug Monit. 1994 Aug;16(4):368-74. doi: 10.1097/00007691-199408000-00006.
Therapeutic drug monitoring data for clozapine were used to study interactions with other drugs. The distribution of the ratio concentration/dose (C/D) of clozapine was compared in four matched groups--patients simultaneously treated with benzodiazepines, patients on drugs that inhibit the cytochrome P450 enzyme CYP2D6, patients taking carbamazepine, and those not taking any of these drugs. No difference was seen among the monotherapy, CYP2D6, and benzodiazepine groups. Patients on carbamazepine had a mean 50% lower C/D than the monotherapy group (p < 0.001), indicating that carbamazepine is an inducer of the metabolism of clozapine. The C/D was inversely correlated to the daily dose of carbamazepine. Intraindividual comparisons in eight patients, with analyses both on and off carbamazepine, confirmed a substantial decrease of the clozapine concentration when carbamazepine was introduced. Four patients treated with clozapine were concomitantly given the antidepressant fluvoxamine. Three of them exhibited a much higher C/D ratio when on fluvoxamine compared with the monotherapy group. Two had their clozapine levels analyzed when on and off fluvoxamine. The dose-normalized clozapine concentration increased by a factor of 5-10 when fluvoxamine was added. We conclude that carbamazepine causes decreased clozapine plasma levels, while fluvoxamine increases the levels. The pathways are not known with certainty, but CYP1A2 may be of major importance for the metabolism of clozapine, since fluvoxamine is a potent inhibitor of this enzyme. A recent panel study suggests that determination of CYP1A2 activity with the caffeine test may be very useful for the dosing of clozapine. The induction of clozapine metabolism by carbamazepine might be partly mediated by CYP3A4.
使用氯氮平的治疗药物监测数据来研究其与其他药物的相互作用。比较了四个匹配组中氯氮平浓度/剂量比（C/D）的分布情况，这四个组分别为：同时接受苯二氮䓬类药物治疗的患者、服用抑制细胞色素P450酶CYP2D6药物的患者、服用卡马西平的患者以及未服用上述任何药物的患者。在单一疗法组、CYP2D6组和苯二氮䓬类药物组之间未观察到差异。服用卡马西平的患者的平均C/D比单一疗法组低50%（p < 0.001），这表明卡马西平是氯氮平代谢的诱导剂。C/D与卡马西平的每日剂量呈负相关。对8名患者进行个体内比较，在服用和停用卡马西平的情况下均进行分析，证实引入卡马西平后氯氮平浓度大幅下降。4名接受氯氮平治疗的患者同时服用了抗抑郁药氟伏沙明。其中3名患者在服用氟伏沙明时的C/D比单一疗法组高得多。2名患者在服用和停用氟伏沙明时对其氯氮平水平进行了分析。添加氟伏沙明后，剂量标准化的氯氮平浓度增加了5至10倍。我们得出结论，卡马西平会导致氯氮平血浆水平降低，而氟伏沙明会使其水平升高。具体途径尚不确定，但CYP1A2可能对氯氮平的代谢起主要作用，因为氟伏沙明是该酶的强效抑制剂。最近的一项小组研究表明，通过咖啡因试验测定CYP1A2活性可能对氯氮平的给药非常有用。卡马西平对氯氮平代谢的诱导作用可能部分由CYP3A4介导。
