Center for Psychopharmacology, Diakonhjemmet Hospital, P.O. Box 85, Vinderen, N-0319 Oslo, Norway.
Drug Metab Dispos. 2012 Sep;40(9):1778-84. doi: 10.1124/dmd.112.045237. Epub 2012 Jun 11.
The antipsychotic drug quetiapine has been approved for the treatment of unipolar and bipolar depression. The antidepressant activity is considered to be mediated by the active metabolite N-desalkylquetiapine, which is mainly formed by CYP3A4. Little is known about the subsequent elimination of this metabolite. Therefore, this study investigated the possible involvement of cytochrome P450 (P450) enzymes in the metabolism of N-desalkylquetiapine. Screening for and interpretation of metabolites were performed by incubating N-desalkylquetiapine in human liver microsomes (HLM) followed by liquid chromatography-tandem mass spectrometry. The possible involvement of P450 enzymes in N-desalkylquetiapine metabolism was evaluated by coincubation of selective P450 inhibitors in HLM and subsequent experiments with recombinant human P450 enzymes. In HLM experiments, three chromatographic peaks were interpreted as possible metabolites of N-desalkylquetiapine, namely, N-desalkylquetiapine sulfoxide, 7-hydroxy-N-desalkylquetiapine, and an unrecognized metabolite (denoted M3). Inhibition of CYP2D6 (by quinidine) reduced formation of 7-hydroxy-N-desalkylquetiapine by 81%, whereas the CYP3A4 inhibitor ketoconazole inhibited formation of N-desalkylquetiapine sulfoxide and M3 by 65 and 34%, respectively. Inhibitors of CYP1A2, CYP2C9, and CYP2C19 showed only limited changes in metabolite formation. In recombinant systems, 7-hydroxy-N-desalkylquetiapine was exclusively formed by CYP2D6, whereas N-desalkylquetiapine sulfoxide and M3 were formed by both CYP3A4 and CYP2D6. Overall, intrinsic clearance of N-desalkylquetiapine was 12-fold higher by recombinant CYP2D6 relative to CYP3A4. In conclusion, N-desalkylquetiapine is metabolized by both CYP2D6 and CYP3A4 in vitro with preference for the former enzyme. The pharmacologically active metabolite, 7-hydroxy-N-desalkylquetiapine, was exclusively formed by CYP2D6, whereas the two other metabolites were mainly formed by CYP3A4.
抗精神病药物喹硫平已获准用于单相和双相抑郁症的治疗。其抗抑郁作用被认为是由主要由 CYP3A4 形成的活性代谢物 N-去烷基喹硫平介导的。关于这种代谢物的后续消除知之甚少。因此，本研究调查了细胞色素 P450（P450）酶在 N-去烷基喹硫平代谢中的可能作用。通过在人肝微粒体（HLM）中孵育 N-去烷基喹硫平，然后进行液相色谱-串联质谱分析来筛选和解释代谢物。通过在 HLM 中同时孵育选择性 P450 抑制剂并随后用重组人 P450 酶进行实验来评估 P450 酶在 N-去烷基喹硫平代谢中的可能作用。在 HLM 实验中，解释为 N-去烷基喹硫平可能的代谢物的三个色谱峰，分别为 N-去烷基喹硫平亚砜、7-羟基-N-去烷基喹硫平和未识别的代谢物（表示为 M3）。CYP2D6 的抑制剂（奎尼丁）将 7-羟基-N-去烷基喹硫平的形成减少了 81%，而 CYP3A4 的抑制剂酮康唑分别将 N-去烷基喹硫平亚砜和 M3 的形成减少了 65%和 34%。CYP1A2、CYP2C9 和 CYP2C19 的抑制剂仅对代谢物的形成产生有限的变化。在重组系统中，7-羟基-N-去烷基喹硫平仅由 CYP2D6 形成，而 N-去烷基喹硫平亚砜和 M3 由 CYP3A4 和 CYP2D6 共同形成。总体而言，与 CYP3A4 相比，重组 CYP2D6 对 N-去烷基喹硫平的内在清除率高 12 倍。结论：N-去烷基喹硫平在体外主要由 CYP2D6 和 CYP3A4 代谢，前者具有优势。具有药理活性的代谢物 7-羟基-N-去烷基喹硫平仅由 CYP2D6 形成，而另外两种代谢物主要由 CYP3A4 形成。
