6-羟基泰素 | 153212-75-0

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 中文名称: 6-羟基泰素
• 中文别名: 6-羟基紫杉醇；6Alpha-羟基紫杉醇
• 英文名称: [3H]-6alpha-Hydroxypaclitaxel
• 英文别名: 6α-hydroxypaclitaxel；6alpha-Hydroxypaclitaxel；[(1S,2S,3R,4S,7R,8S,9R,10S,12R,15S)-4,12-diacetyloxy-15-[(2R,3S)-3-benzamido-2-hydroxy-3-phenylpropanoyl]oxy-1,8,9-trihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.03,10.04,7]heptadec-13-en-2-yl] benzoate
• CAS: 153212-75-0
• 化学式: C₄₇H₅₁NO₁₅
• 分子量: 869.92
• InChiKey: NDCWHEDPSFRTDA-FJMWQILYSA-N

物化性质

• 熔点：
  177-180°C
• 沸点：
  979.8±65.0 °C(Predicted)
• 密度：
  1.43±0.1 g/cm3(Predicted)
• 溶解度：
  DMSO（微溶）、乙酸乙酯（微溶）、甲醇（微溶）

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  63
• 可旋转键数：
  14
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  242
• 氢给体数：
  5
• 氢受体数：
  15

安全信息

• 储存条件：
  2-8°C

制备方法与用途

6α-羟基紫杉醇是紫杉醇的主要代谢产物，它对有机阴离子转运多肽1B1/SLCO1B1（OATP1B1）具有时间依赖性的抑制作用，其效力与紫杉醇相似；然而，它不再表现出对OATP1B3的时间依赖性抑制。6α-羟基紫杉醇可用于癌症研究。

反应信息

• 作为产物：
  描述：

  紫杉醇 在 cytochrome P 2C_8.1 、 还原型辅酶II(NADPH)四钠盐 、 magnesium chloride 作用下， 以 aq. buffer 为溶剂， 生成 6-羟基泰素
  参考文献：
  名称：

  CYP2C8基因多态性对紫杉醇，瑞格列奈和布洛芬对映体体外羟基化代谢的影响。

  摘要：

  CYP2C8在紫杉醇，瑞格列奈和布洛芬等各种药物的代谢中起重要作用。CYP2C8基因的多态性显示影响紫杉醇，瑞格列奈和布洛芬对映体药代动力学的个体差异。在这项研究中，三种CYP2C8等位基因变体（CYP2C8.2，CYP2C8.3和CYP2C8.4）和野生型CYP2C8（CYP2C8.1）首次与人细胞色素P450氧化还原酶（POR）和细胞色素b5共表达通过使用杆状病毒辅助的昆虫细胞表达系统。此外，评估了CYP2C8等位基因的基因型-表型相关性对紫杉醇，瑞格列奈和布洛芬对映体代谢的影响。紫杉醇的CYP2C8.2，CYP2C8.3和CYP2C8.4的CLint值分别为CYP2C8.1的47.7％，64.3％和30.2％（p <0.01）。瑞格列奈的CYP2C8.2和CYP2C8.4的CLint值分别是CYP2C8.1的77.9％和80.2％（p <0.05），而CYP2C8.3的CLint值是CYP2C8的1

  DOI：

  10.1002/bdd.1842

文献信息

• 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。
• Identification of human cytochrome P 450 s that metabolise anti-parasitic drugs and predictions of in vivo drug hepatic clearance from in vitro data
  作者：Xue-Qing Li、Anders Bj�rkman、Tommy B. Andersson、Lars L. Gustafsson、Collen M. Masimirembwa

  DOI：10.1007/s00228-003-0636-9

  日期：2003.9.1

  Objective. Knowledge about the metabolism of anti-parasitic drugs (APDs) will be helpful in ongoing efforts to optimise dosage recommendations in clinical practise. This study was performed to further identify the cytochrome P-450 (CYP) enzymes that metabolise major APDs and evaluate the possibility of predicting in vivo drug clearances from in vitro data.Methods. In vitro systems, rat and human liver microsomes (RLM, HLM) and recombinant cytochrome P-450 (rCYP), were used to determine the intrinsic clearance (CLint) and identify responsible CYPs and their relative contribution in the metabolism of 15 commonly used APDs.Results and discussion. CLint determined in RLM and HLM showed low (r(2)=0.50) but significant (P<0.01) correlation. The CLint values were scaled to predict in vivo hepatic clearance (CLH) using the 'venous equilibrium model'. The number of compounds with in vivo human CL data after intravenous administration was low (n=8), and the range of CL values covered by these compounds was not appropriate for a reasonable quantitative in vitro-in vivo correlation analysis. Using the CLH predicted from the in vitro data, the compounds could be classified into three different categories: high-clearance drugs (>70% liver blood flow; amodiaquine, praziquantel, albendazole, thiabendazole), low-clearance drugs (<30% liver blood flow; chloroquine, dapsone, diethylcarbamazine, pentamidine, primaquine, pyrantel, pyrimethamine, tinidazole) and intermediate clearance drugs (artemisinin, artesunate, quinine). With the exception of artemisinin, which is a high clearance drug in vivo, all other compounds were classified using in vitro data in agreement with in vivo observations. We identified hepatic CYP enzymes responsible for metabolism of some compounds (praziquantel-1A2, 2C19, 3A4; primaquine-1A2, 3A4; chloroquine-2C8, 2D6, 3A4; artesunate-2A6; pyrantel-2D6). For the other compounds, we confirmed the role of previously reported CYPs for their metabolism and identified other CYPs involved which had not been reported before.Conclusion. Our results show that it is possible to make in vitro-in vivo predictions of high, intermediate and low CLint drug categories. The identified CYPs for some of the drugs provide a basis for how these drugs are expected to behave pharmacokinetically and help in predicting drug-drug interactions in vivo.
• 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
• Structural and functional insights into polymorphic enzymes of cytochrome P450 2C8
  作者：Hualin Jiang、Fangfang Zhong、Lu Sun、Weiyue Feng、Zhong-Xian Huang、Xiangshi Tan

  DOI：10.1007/s00726-010-0743-8

  日期：2011.4

  The cytochrome P450 (CYP) superfamily plays a key role in the oxidative metabolism of a wide range of drugs and exogenous chemicals. CYP2C8 is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel in the human liver. Nearly all previous works about polymorphic variants of CYP2C8 were focused on unpurified proteins, either cells or human liver microsomes; therefore their structure-function relationships were unclear. In this study, two polymorphic enzymes of CYP2C8 (CYP2C8.4 (I264M) and CYP2C8 P404A) were expressed in E. coli and purified. Metabolic activities of paclitaxel by the two purified polymorphic enzymes were observed. The activity of CYP2C8.4 was 25% and CYP2C8 P404A was 30% of that of WT CYP2C8, respectively. Their structure-function relationships were systematically investigated for the first time. Paclitaxel binding ability of CYP2C8.4 increased about two times while CYP2C8 P404A decreased about two times than that of WT CYP2C8. The two polymorphic mutant sites of I264 and P404, located far from active site and substrate binding sites, significantly affect heme and/or substrate binding. This study indicated that two important nonsubstrate recognition site (SRS) residues of CYP2C8 are closely related to heme binding and/or substrate binding. This discovery could be valuable for explaining clinically individual differences in the metabolism of drugs and provides instructed information for individualized medication.