细胞色素P450 1A2（CYP1A2）和细胞色素P450 3A4（CYP3A4）在氯氮平代谢中的作用。
The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine.
作者信息
Eiermann B, Engel G, Johansson I, Zanger U M, Bertilsson L
机构信息
Department of Medical Laboratory Sciences and Technology, Karolinska Institutet, Huddinge University Hospital, Sweden.
出版信息
Br J Clin Pharmacol. 1997 Nov;44(5):439-46. doi: 10.1046/j.1365-2125.1997.t01-1-00605.x.
AIMS
Clozapine (CLZ), an atypical neuroleptic with a high risk of causing agranulocytosis, is metabolized in the liver to desmethylclozapine (DCLZ) and clozapine N-oxide (CLZ-NO). This study investigated the involvement of different CYP isoforms in the formation of these two metabolites.
METHODS
Human liver microsomal incubations, chemical inhibitors, specific antibodies, and different cytochrome P450 expression systems were used.
RESULTS
Km and Vmax values determined in human liver microsomes were lower for the demethylation (61 +/- 21 microM, 159 +/- 42 pmol min(-1) mg protein(-1) mean +/- s.d.; n = 4), than for the N-oxidation of CLZ (308 +/- 1.5 microM, 456 +/- 167 pmol min(-1) mg protein(-1); n = 3). Formation of DCLZ was inhibited by fluvoxamine (53 +/- 28% at 10 microM), triacetyloleandomycin (33 +/- 15% at 10 microM), and ketoconazole (51 +/- 28% at 2 microM) and by antibodies against CYP1A2 and CYP3A4. CLZ-NO formation was inhibited by triacetyloleandomycin (34 +/- 16% at 10 microM) and ketoconazole (51 +/- 13% at 2 microM), and by antibodies against CYP3A4. There was a significant correlation between CYP3A content and DCLZ formation in microsomes from 15 human livers (r=0.67; P=0.04). A high but not significant correlation coefficient was found for CYP3A content and CLZ-NO formation (r=0.59; P=0.09). Using expression systems it was shown that CYP1A2 and CYP3A4 formed DCLZ and CLZ-NO. Km and Vmax values were lower in the CYP1A2 expression system compared to CYP3A4 for both metabolic reactions.
CONCLUSIONS
It is concluded that CYP1A2 and CYP3A4 are involved in the demethylation of CLZ and CYP3A4 in the N-oxidation of CLZ. Close monitoring of CLZ plasma levels is recommended in patients treated at the same time with other drugs affecting these two enzymes.
目的
氯氮平（CLZ）是一种非典型抗精神病药物，有导致粒细胞缺乏症的高风险，在肝脏中代谢为去甲基氯氮平（DCLZ）和氯氮平氮氧化物（CLZ - NO）。本研究调查了不同细胞色素P450（CYP）同工酶在这两种代谢物形成过程中的作用。
方法
采用人肝微粒体孵育、化学抑制剂、特异性抗体及不同的细胞色素P450表达系统。
结果
人肝微粒体中去甲基化反应的米氏常数（Km）和最大反应速度（Vmax）值（61±21μM，159±42 pmol min⁻¹mg蛋白⁻¹，平均值±标准差；n = 4）低于氯氮平氮氧化反应（308±1.5μM，456±167 pmol min⁻¹mg蛋白⁻¹；n = 3）。氟伏沙明（10μM时抑制率为53±28%）、三乙酰竹桃霉素（10μM时抑制率为33±15%）、酮康唑（2μM时抑制率为51±28%）以及抗CYP1A2和CYP3A4抗体可抑制DCLZ的形成。三乙酰竹桃霉素（10μM时抑制率为34±16%）、酮康唑（2μM时抑制率为51±13%）以及抗CYP3A4抗体可抑制CLZ - NO的形成。15例人肝脏微粒体中CYP3A含量与DCLZ形成之间存在显著相关性（r = 0.67；P = 0.04）。CYP3A含量与CLZ - NO形成之间的相关系数较高但无统计学意义（r = 0.59；P = 0.09）。利用表达系统表明CYP1A2和CYP3A4可形成DCLZ和CLZ - NO。两种代谢反应中，CYP1A2表达系统中的Km和Vmax值均低于CYP3A4表达系统。
结论
得出结论，CYP1A2和CYP3A4参与氯氮平的去甲基化反应，CYP3A4参与氯氮平的氮氧化反应。建议同时接受影响这两种酶的其他药物治疗的患者密切监测氯氮平的血浆水平。
Zotero 插件