(S)-4-羟基美芬妥英 | 82695-93-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑烷类
• 中文名称: (S)-4-羟基美芬妥英
• 英文名称: 4'-hydroxymephenytoin
• 英文别名: 4'-hydroxy-S-mephenytoin；(S)-4'-Hydroxymephenytoin；4′-hydroxymephenytoin；[14C]-(S)-4'-Hydroxymephenytoin；(5S)-5-Ethyl-5-(4-hydroxyphenyl)-3-methylimidazolidine-2,4-dione
• CAS: 82695-93-0
• 化学式: C₁₂H₁₄N₂O₃
• 分子量: 234.255
• InChiKey: OQPLORUDZLXXPD-LBPRGKRZSA-N

物化性质

• 熔点：
  188-191°C
• 密度：
  1.249±0.06 g/cm3(Predicted)
• 溶解度：
  可溶于水基（轻微）、DMSO（轻微）、乙酸乙酯（轻微）、甲醇（轻微）

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  69.6
• 氢给体数：
  2
• 氢受体数：
  3

ADMET

代谢

4'-羟基美芬妥因是S-美芬妥因的人类已知代谢物。

4'-Hydroxymephenytoin is a known human metabolite of S-Mephenytoin.

来源:NORMAN Suspect List Exchange

反应信息

• 作为产物：
  描述：

  甲秦皮素 在 CYP₂C₁₉-genotyped human liver microsomes 作用下， 反应 0.67h， 生成 (S)-4-羟基美芬妥英
  参考文献：
  名称：

  细胞色素P450变异对哌替啶N-去甲基化对神经毒性代谢物诺哌啶的影响。

  摘要：

  哌替啶是一种阿片类镇痛药，经过N-去甲基化作用形成神经毒性代谢物诺哌啶。先前的研究表明，哌替啶N-去甲基化是由细胞色素P450 2B6（CYP2B6），CYP3A4和CYP2C19.2催化的。这项研究的目的是检查相对P450对哌啶N-去甲基化的贡献，并评估CYP2C19多态性对去甲张定的影响。使用重组P450酶，选择性化学抑制剂，酶动力学分析以及与CYP2C19基因分型的人肝微粒体的相关性分析进行实验。3。在重组CYP2B6和CYP2C19之间，哌替啶N-去甲基化的催化效率（kcat / Km）相似，但明显低于CYP3A4.4。在CYP2C19基因型人肝微粒体中，Normeperidine的形成与CYP2C19活性显着相关（S-美芬妥英4′-羟基化）。5。CYP2C19抑制剂（+）-N-3-苄基肾上腺素和CYP3A抑制剂酮康唑显着减少了具有高CYP2C19活性的单个供体的微粒体去甲定啶生成

  DOI：

  10.1080/00498254.2019.1599465

文献信息

• Inhibition of Human Drug Metabolizing Cytochrome P450 by Buprenorphine.
  作者：Ken Umehara、Yoshihiko Shimokawa、Gohachiro Miyamoto

  DOI：10.1248/bpb.25.682

  日期：——

  The effects of buprenorphine, a powerful mixed agonist/antagonist analgesic, on several cytochrome P450 (CYP) isoform specific reactions in human liver microsomes were investigated to predict drug interaction of buprenorphine in vivo from in vitro data. The following eight CYP-catalytic reactions were used in this study: CYP1A1/2-mediated 7-ethoxyresorufin O-deethylation, CYP2A6-mediated coumarin 7-hydroxylation, CYP2B6-mediated 7-benzyloxyresorufin O-debenzylation, CYP2C8/9-mediated tolbutamide methylhydroxylation, CYP2C19-mediated S-mephenytoin 4-hydroxylation, CYP2D6-mediated bufuralol 1′-hydroxylation, CYP2E1-mediated chlorzoxazone 6-hydroxylation, and CYP3A4-mediated testosterone 6β-hydroxylation. Buprenorphine strongly inhibited the CYP3A4- and CYP2D6-catalyzed reactions with Ki values of 14.7 μM and 21.4 μM, respectively. The analgesic also weakly inhibited specific reactions catalyzed by CYP1A1/2 (Ki=132 μM), CYP2B6 (Ki=133 μM), CYP2C19 (Ki=146 μM), CYP2C8/9 (IC50>300 μM), and CYP2E1 (IC50>300 μM), but not CYP2A6 mediated pathway. In consideration of the Ki values obtained in this study and the therapeutic concentration of buprenorphine in human plasma, buprenorphine would not be predicted to cause clinically significant interactions with other CYP-metabolized drugs.

  本研究调查了强效混合激动剂/拮抗剂镇痛药丁丙诺啡在人肝微粒体中对几种细胞色素P450（CYP）同工酶特异性反应的影响，旨在从体外数据预测丁丙诺啡在体内的药物相互作用。本研究使用了以下八种CYP催化反应：CYP1A1/2介导的7-乙氧基罗丹明O-脱乙基化、CYP2A6介导的香豆素7-羟化、CYP2B6介导的7-苄氧基罗丹明O-脱苄基化、CYP2C8/9介导的甲苯磺丁脲甲基羟化、CYP2C19介导的S-美芬妥英4-羟化、CYP2D6介导的布非洛尔1′-羟化、CYP2E1介导的氯唑沙宗6-羟化和CYP3A4介导的睾酮6β-羟化。丁丙诺啡对CYP3A4和CYP2D6催化反应显示出强烈抑制作用，Ki值分别为14.7 μM和21.4 μM。该镇痛药还对CYP1A1/2（Ki=132 μM）、CYP2B6（Ki=133 μM）、CYP2C19（Ki=146 μM）、CYP2C8/9（IC50>300 μM）和CYP2E1（IC50>300 μM）介导的特异性反应表现出弱抑制作用，但不包括CYP2A6介导的通路。综合本研究获得的Ki值和丁丙诺啡在人血浆中的治疗浓度，预计丁丙诺啡不会引起与其他CYP代谢药物临床意义上的显著相互作用。
• Impact of cytochrome P450 variation on meperidine<i>N</i>-demethylation to the neurotoxic metabolite normeperidine
  作者：Jessica L. Murray、Susan L. Mercer、Klarissa D. Jackson

  DOI：10.1080/00498254.2019.1599465

  日期：2020.2.1

  1. Meperidine is an opioid analgesic that undergoes N-demethylation to form the neurotoxic metabolite normeperidine. Previous studies indicate that meperidine N-demethylation is catalyzed by cytochrome P450 2B6 (CYP2B6), CYP3A4, and CYP2C19.2. The purpose of this study was to examine the relative P450 contributions to meperidine N-demethylation and to evaluate the effect of CYP2C19 polymorphism on

  哌替啶是一种阿片类镇痛药，经过N-去甲基化作用形成神经毒性代谢物诺哌啶。先前的研究表明，哌替啶N-去甲基化是由细胞色素P450 2B6（CYP2B6），CYP3A4和CYP2C19.2催化的。这项研究的目的是检查相对P450对哌啶N-去甲基化的贡献，并评估CYP2C19多态性对去甲张定的影响。使用重组P450酶，选择性化学抑制剂，酶动力学分析以及与CYP2C19基因分型的人肝微粒体的相关性分析进行实验。3。在重组CYP2B6和CYP2C19之间，哌替啶N-去甲基化的催化效率（kcat / Km）相似，但明显低于CYP3A4.4。在CYP2C19基因型人肝微粒体中，Normeperidine的形成与CYP2C19活性显着相关（S-美芬妥英4′-羟基化）。5。CYP2C19抑制剂（+）-N-3-苄基肾上腺素和CYP3A抑制剂酮康唑显着减少了具有高CYP2C19活性的单个供体的微粒体去甲定啶生成
• Evaluation of Cytochrome P450 Selectivity for Hydralazine as an Aldehyde Oxidase Inhibitor for Reaction Phenotyping
  作者：Xin Yang、Nathaniel Johnson、Li Di

  DOI：10.1016/j.xphs.2018.11.007

  日期：2019.4

  Hydralazine has been reported as a selective mechanism-based inactivator of aldehyde oxidase (AO) and it is widely used in the pharmaceutical industry for reaction phenotyping to estimate fraction metabolized by AO and to identify AO substrates. In this study, however, hydralazine was found to inhibit CYP1A2, 2B6, 2D6, and 3A in human suspension hepatocytes under reaction phenotyping assay conditions, at

  据报道，肼屈嗪是一种基于选择性机理的醛氧化酶（AO）灭活剂，它在制药行业中广泛用于反应表型分析，以评估AO代谢的组分并鉴定AO底物。然而，在这项研究中，发现肼苯哒嗪在化学表型测定条件下以化学敲除大多数AO活性（≥50μM）的浓度抑制人悬液肝细胞中的CYP1A2、2B6、2D6和3A。此外，肼屈嗪是CYP1A2的时间依赖性抑制剂。基于这些发现，在体外研究中使用肼屈嗪作为AO抑制剂时需要采取预防措施，因为由AO代谢的级分可能被高估，并且在识别AO底物​​时出现假阳性的可能性增加。
• Cytochrome P450 Metabolic Activities in the Small Intestine of Cynomolgus Macaques Bred in Cambodia, China, and Indonesia
  作者：Yasuharu Nakanishi、Hiroyuki Yamashita、Tsuyoshi Yoshikawa、Takeshi Tominaga、Koichiro Nojiri、Yoshiharu Sunaga、Atsunobu Muneoka、Kazuhide Iwasaki、Masahiro Utoh、Chika Nakamura、Hiroshi Yamazaki、Yasuhiro Uno

  DOI：10.2133/dmpk.dmpk-13-nt-031

  日期：——

  Cynomolgus macaques, used in drug metabolism studies due to their evolutionary closeness to humans, are mainly bred in Asian countries, including Cambodia, China, and Indonesia. Cytochromes P450 (P450s) are important drug-metabolizing enzymes, present in the liver and small intestine, major drug metabolizing organs. Previously, our investigation did not find statistically significant differences in hepatic P450 metabolic activities measured in cynomolgus macaques bred in Cambodia (MacfaCAM) and China (MacfaCHN). In the present study, P450 metabolic activity was investigated in the small intestine of MacfaCAM and MacfaCHN, and cynomolgus macaques bred in Indonesia (MacfaIDN) using P450 substrates, including 7-ethoxyresorufin, coumarin, bupropion, paclitaxel, diclofenac, S-mephenytoin, bufuralol, chlorzoxazone, and testosterone. The results indicated that P450 metabolic activity of the small intestine was not statistically significantly different (<2.0-fold) in MacfaCAM, MacfaCHN, and MacfaIDN. In addition, statistically significant sex differences were not observed (<2.0-fold) in any P450 metabolic activity in MacfaCAM as supported by mRNA expression results. These results suggest that P450 metabolic activity of the small intestine does not significantly differ statistically among MacfaCAM, MacfaCHN, and MacfaIDN.
• <i>In vitro</i> evaluations for pharmacokinetic drug-drug interactions of a novel serotonin-dopamine activity modulator, brexpiprazole
  作者：Hiroyuki Sasabe、Toshihisa Koga、Masayuki Furukawa、Masayuki Matsunaga、Katsunori Sasahara、Kenta Hashizume、Yoshihiro Oozone、Immaculate Amunom、Mikako Torii、Ken Umehara、Eiji Kashiyama、Kenji Takeuchi

  DOI：10.1080/00498254.2021.1897898

  日期：2021.5.4