2-Hydroxyzotepine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并硫平类
• 英文名称: 2-Hydroxyzotepine
• 英文别名: 3-Chloro-5-[2-(dimethylamino)ethoxy]benzo[b][1]benzothiepin-8-ol
• 化学式: C₁₈H₁₈ClNO₂S
• 分子量: 347.865
• InChiKey: MCQGRTOFLHWZAG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  58
• 氢给体数：
  1
• 氢受体数：
  4

ADMET

代谢

2-羟基佐替平是佐替平在人身体内已知的代谢物。

2-hydroxy-zotepine is a known human metabolite of zotepine.

来源:NORMAN Suspect List Exchange

反应信息

• 作为产物：
  描述：

  佐替平 在 human liver microsomes 、 NADPH-generating system 作用下， 以 甲醇 、 phosphate buffer 为溶剂， 反应 0.17h， 生成 Norzotepine 、 Zotepine S-oxide 、 3-Hydroxyzotepine 、 2-Hydroxyzotepine
  参考文献：
  名称：

  Identification of cytochrome P450 enzymes involved in the metabolism of zotepine, an antipsychotic drug, in human liver microsomes

  摘要：

  1. Studies using human liver microsomes and recombinant human cytochrome P450 (P450) enzymes and flavin-containing monooxygenase (FMO) were performed to identify the enzymes responsible for the formation of zotepine metabolites in man.2. Human liver microsomes produced four metabolites and a tentative order of importance was: norzotepine, 3-hydroxyzotepine, zotepine S-oxide and 2-hydroxyzotepine. Zotepine N-oxide was also detected, but it could not bt quantified.3. The rates of formation of the major metabolite, norzotepine, and zotepine S-oxide (at a substrate concentration of 20 mu M) were significantly correlated with the testosterone 6 beta-hydroxylase activities and CYP3A4 contents of the 12 different human liver microsomal samples. Inhibition studies with P450 enzyme selective inhibitors and anti-rat CYP3A2 antibodies also indicated a predominant role of CYP3A4 in the formation of norzotepine and zotepine S-oxide. Furafylline and sulphaphenazole inhibited the N-demethylation of zotepine by up to similar to 30%.4. Correlation and inhibition data for the 2- and 3-hydroxylation of zotepine were consistent with the predominant role of CYP1A2 and 2D6 in the formation of these metabolites, respectively.5. Recombinant CYP1A1, 1A2, 2B6, 2C19, 3A4 and 3A5 efficiently catalysed N-demethylation of zotepine. CYP1A1, 1A2, 2B6 and 3A4 were also active for S-oxidation. CYP1A2 and 2D6*1-Val374 efficiently produced 2-hydroxyzotepine and 3-hyroxyzotepine, respectively. Recombinant human FMO3 did not catalyse zotepine S-oxidation.6. These results suggest that both the N-demethylation and S-oxidation of zotepine are mediated mainly by CYP3A4, and that CYP1A2 and 2D6 play an important role in the 2- and 3-hydroxylation of zotepine, respectively.

  DOI：

  10.1080/004982599238623

文献信息

• JPS568378A
  申请人：——

  公开号：JPS568378A

  公开（公告）日：1981-01-28
• Identification of cytochrome P450 enzymes involved in the metabolism of zotepine, an antipsychotic drug, in human liver microsomes
  作者：T. SHIRAGA、H. KANEKO、K. IWASAKI、Z. TOZUKA、A. SUZUKI、T. HATA

  DOI：10.1080/004982599238623

  日期：1999.1

  1. Studies using human liver microsomes and recombinant human cytochrome P450 (P450) enzymes and flavin-containing monooxygenase (FMO) were performed to identify the enzymes responsible for the formation of zotepine metabolites in man.2. Human liver microsomes produced four metabolites and a tentative order of importance was: norzotepine, 3-hydroxyzotepine, zotepine S-oxide and 2-hydroxyzotepine. Zotepine N-oxide was also detected, but it could not bt quantified.3. The rates of formation of the major metabolite, norzotepine, and zotepine S-oxide (at a substrate concentration of 20 mu M) were significantly correlated with the testosterone 6 beta-hydroxylase activities and CYP3A4 contents of the 12 different human liver microsomal samples. Inhibition studies with P450 enzyme selective inhibitors and anti-rat CYP3A2 antibodies also indicated a predominant role of CYP3A4 in the formation of norzotepine and zotepine S-oxide. Furafylline and sulphaphenazole inhibited the N-demethylation of zotepine by up to similar to 30%.4. Correlation and inhibition data for the 2- and 3-hydroxylation of zotepine were consistent with the predominant role of CYP1A2 and 2D6 in the formation of these metabolites, respectively.5. Recombinant CYP1A1, 1A2, 2B6, 2C19, 3A4 and 3A5 efficiently catalysed N-demethylation of zotepine. CYP1A1, 1A2, 2B6 and 3A4 were also active for S-oxidation. CYP1A2 and 2D6*1-Val374 efficiently produced 2-hydroxyzotepine and 3-hyroxyzotepine, respectively. Recombinant human FMO3 did not catalyse zotepine S-oxidation.6. These results suggest that both the N-demethylation and S-oxidation of zotepine are mediated mainly by CYP3A4, and that CYP1A2 and 2D6 play an important role in the 2- and 3-hydroxylation of zotepine, respectively.