Nefazodone, meta-chlorophenylpiperazine, and their metabolites in vitro: cytochromes mediating transformation, and P450-3A4 inhibitory actions.
Nefazodone, meta-chlorophenylpiperazine, and their metabolites in vitro: cytochromes mediating transformation, and P450-3A4 inhibitory actions.
复制标题
奈法唑酮、间氯苯基哌嗪及其体外代谢物：细胞色素介导转化和 P450-3A4 抑制作用。
DOI：
10.1007/s002130051039
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发表时间：
1999
影响因子：
3.4
通讯作者：
Shader,RI
中科院分区：
文献类型：
--
作者：
vonMoltke,LL;Greenblatt,DJ;Granda,BW;Grassi,JM;Schmider,J;Harmatz,JS;Shader,RI
基本原理：了解抗抑郁药的生物转化机制及其与其他药物相互作用的能力，与合理的临床精神药理学直接相关。目的：测定奈法唑酮代谢中的人细胞色素P450，以及奈法唑酮及其代谢产物对人P450- 3A的抑制活性。利用人肝微粒体和异源表达的人细胞色素在体外研究了奈法唑酮向其代谢产物的生物转化以及间氯苯基哌嗪（mCPP）向对羟基mCPP的生物转化。奈法唑酮及其代谢产物也被测试为阿普唑仑羟基化的抑制剂，反映细胞色素P450-3A亚型的活性。结果：mCPP和两个羟基化衍生物是奈法唑酮通过肝微粒体形成的主要代谢产物。代谢产物的产生强烈抑制酮康唑或三乙酰竹桃霉素（相对特异性P450-3A抑制剂），并通过抗P450 -3A抗体。只有异源表达的人P450- 3A 4介导母体化合物形成奈法唑酮代谢物。奈法唑酮、羟基奈法唑酮和对羟基奈法唑酮是强3A抑制剂，比去甲氟西汀和氟伏沙明更有效，但效力低于酮康唑。三唑二酮代谢物和mCPP具有较弱或可忽略的3A抑制活性。异源表达的P450- 2D 6介导mCPP形成对羟基-mCPP;在肝微粒体中，该反应被奎尼丁，一个相对特异的2D 6抑制剂强烈reproditable。结论：奈法唑酮的复杂的平行生物转化途径主要由人细胞色素P450-3A介导，而mCPP的清除是由P450- 2D 6介导的。奈法唑酮及其两种羟基化代谢产物是有效的3A抑制剂，可解释奈法唑酮与3A底物药物（如三唑仑和阿普唑仑）的药代动力学药物相互作用。
Rationale: Understanding of the mechanisms of biotransformation of antidepressant drugs, and of their capacity to interact with other medications, is of direct relevance to rational clinical psychopharmacology.Objectives: To determine the human cytochromes P450 mediating the metabolism of nefazodone, and the inhibitory activity of nefazodone and metabolites versus human P450–3A.Methods: Biotransformation of nefazodone to its metabolic products, and of meta-chlorophenylpiperazine (mCPP) to para-hydroxy-mCPP, was studied in vitro using human liver microsomes and heterologously expressed human cytochromes. Nefazodone and metabolites were also tested as inhibitors of alprazolam hydroxylation, reflecting activity of cytochrome P450–3A isoforms.Results: mCPP and two hydroxylated derivatives were the principal metabolites formed from nefazodone by liver microsomes. Metabolite production was strongly inhibited by ketoconazole or troleandomycin (relatively specific P450–3A inhibitors), and by an anti-P450-3A antibody. Only heterologously expressed human P450-3A4 mediated formation of nefazodone metabolites from the parent compound. Nefazodone, hydroxy-nefazodone, and para-hydroxy-nefazodone were strong 3A inhibitors, being more potent than norfluoxetine and fluvoxamine, but less potent than ketoconazole. The triazoledione metabolite and mCPP had weak or negligible 3A-inhibiting activity. Formation of para-hydroxy-mCPP from mCPP was mediated by heterologously expressed P450-2D6; in liver microsomes, the reaction was strongly inhibitable by quinidine, a relatively specific 2D6 inhibitor.Conclusion: The complex parallel biotransformation pathways of nefazodone are mediated mainly by human cytochrome P450-3A, whereas clearance of mCPP is mediated by P450-2D6. Nefazodone and two of its hydroxylated metabolites are potent 3A inhibitors, accounting for pharmacokinetic drug interactions of nefazodone with 3A substrate drugs such as triazolam and alprazolam.