Norfluoxetine (hydrochloride)
(Synonyms: 去甲氟西汀,Desmethylfluoxetine) 目录号 : GC44451An active metabolite of fluoxetine
Cas No.:57226-68-3
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Norfluoxetine is an active metabolite of the antidepressant fluoxetine that inhibits serotonin uptake with a pKi value of 7.35 [1] . The S-enantiomer of norfluoxetine has 20-times higher serotonin reuptake blocking potency than the R-enantiomer (pKis = 7.86 versus 6.51, respectively).[1][2]
Reference:
[1]. Wong, D.T., Bymaster, F.P., Reid, L.R., et al. Norfluoxetine enantiomers as inhibitors of serotonin uptake in rat brain. Neuropsychopharmacology 8(4), 337-344 (1993).
[2]. Hiemke, C., and Härtter, S. Pharmacokinetics of selective serotonin reuptake inhibitors. Pharmacology & Therapeutics 85(1), 11-28 (2000).
| Cas No. | 57226-68-3 | SDF | |
| 别名 | 去甲氟西汀,Desmethylfluoxetine | ||
| 化学名 | γ-[4-(trifluoromethyl)phenoxy]-benzenepropanamine, monohydrochloride | ||
| Canonical SMILES | NCCC(C1=CC=CC=C1)OC2=CC=C(C(F)(F)F)C=C2.Cl | ||
| 分子式 | C16H16F3NO•HCl | 分子量 | 331.8 |
| 溶解度 | 30mg/mL in ethanol, 30mg/mL in DMSO, 30mg/mL in DMF | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.0139 mL | 15.0693 mL | 30.1386 mL |
| 5 mM | 0.6028 mL | 3.0139 mL | 6.0277 mL |
| 10 mM | 0.3014 mL | 1.5069 mL | 3.0139 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Clinical pharmacokinetics of fluoxetine
Clin Pharmacokinet 1994 Mar;26(3):201-14.PMID:8194283DOI:10.2165/00003088-199426030-00004.
Fluoxetine is well absorbed after oral intake, is highly protein bound, and has a large volume of distribution. The elimination half-life of fluoxetine is about 1 to 4 days, while that of its metabolite Norfluoxetine ranges from 7 to 15 days. Fluoxetine has a nonlinear pharmacokinetic profile. Therefore, the drug should be used with caution in patients with a reduced metabolic capability (i.e. hepatic dysfunction). In contrast with its effect on the pharmacokinetics of other antidepressants, age does not affect fluoxetine pharmacokinetics. This finding together with the better tolerability profile of fluoxetine (compared with tricyclic antidepressants) makes this drug particularly suitable for use in elderly patients with depression. Furthermore, the pharmacokinetics of fluoxetine are not affected by either obesity or renal impairment. On the basis of results of plasma concentration-clinical response relationship studies, there appears to be a therapeutic window for fluoxetine. Concentrations of fluoxetine plus Norfluoxetine above 500 micrograms/L appear to be associated with a poorer clinical response than lower concentrations. Fluoxetine interacts with some other drugs. Concomitant administration of fluoxetine increased the blood concentrations of antipsychotics or antidepressants. The interactions between fluoxetine and lithium, tryptophan and monoamine oxidase inhibitors, in particular, are potentially serious, and can lead to the 'serotonergic syndrome'. This is because of synergistic pharmacodynamic effects and the influence of fluoxetine on the bioavailability of these compounds.
Postmortem serum and tissue redistribution of fluoxetine and Norfluoxetine in dogs following oral administration of fluoxetine hydrochloride (Prozac)
J Forensic Sci 1997 Sep;42(5):812-6.PMID:9304827doi
Antemortem serum and postmortem serum and tissues were evaluated to determine if postmortem redistribution of the antidepressant, fluoxetine (Prozac) and its major active metabolite, Norfluoxetine, occurred in dogs following oral administration of fluoxetine hydrochloride. Beagle dogs (four males) received daily oral doses of 10 mg fluoxetine/kg for five days. Antemortem serum concentrations of fluoxetine and Norfluoxetine were determined 3 and 24 h following administration of the first four daily doses of fluoxetine and 3 h after the fifth dose in order to monitor for steady-state serum concentrations of parent and metabolite prior to postmortem serum concentration determinations. Antemortem serum concentrations of fluoxetine and Norfluoxetine 3 h postdose on Day 5 ranged from 530 to 1210 ng/mL and 1460 to 1980 ng/ mL, respectively. Immediately following the 3 h blood sample on Day 5, each dog was euthanized. Serum concentrations of fluoxetine and Norfluoxetine were determined from blood samples collected from the vena cava, heart, and clotted blood within the heart at 2 h after death in two dogs and 12 h after death in the remaining two dogs. Similarly, tissue concentrations of fluoxetine and Norfluoxetine in heart, liver, and lung were determined 2 and 12 h postmortem. Serum concentrations of fluoxetine and Norfluoxetine from the vena cava and heart 2 h postmortem were 2.2- to 6.0-fold and 2.3- to 3.6-fold higher, respectively, than antemortem serum concentrations. Similarly, serum concentrations of fluoxetine and Norfluoxetine from vena cava and heart 12 h postmortem were 1.3- to 3.5-fold and 1.7- to 3.3-fold higher, respectively, than antemortem serum concentrations. However, 2-h and 12-h postmortem serum concentrations of fluoxetine and Norfluoxetine from clotted blood within the heart were equal to or less than levels determined in antemortem serum. Results from 2-h and 12-h postmortem average tissue concentrations of fluoxetine and Norfluoxetine in heart, liver, and lung demonstrated that fluoxetine and Norfluoxetine concentrations in myocardium were similar 2 h and 12 h postmortem. However, in liver, fluoxetine concentrations decreased 39% and Norfluoxetine concentrations decreased 23% from 2 h to 12 h postmortem. Even greater postmortem decreases in fluoxetine and Norfluoxetine concentrations were observed in lung. Fluoxetine and Norfluoxetine concentrations in lung decreased 49% and 39%, respectively, from 2 h to 12 h postmortem. In conclusion, this study demonstrated that fluoxetine and Norfluoxetine undergo postmortem redistribution in the dog. Furthermore, postmortem serum concentrations appear to be dependent on the sample site and the degree of coagulation of the blood. Finally, postmortem decreases in concentrations of fluoxetine and Norfluoxetine in liver and lung may, in part, explain the observed increase in serum concentrations at 2 and 12 h postmortem.
Antidepressants and Antipsychotics in Human Pregnancy: Transfer Across the Placenta and Opportunities for Modeling Studies
J Clin Pharmacol 2022 Sep;62 Suppl 1:S115-S128.PMID:36106784DOI:10.1002/jcph.2108.
There is limited information about the transfer of antidepressants and antipsychotics across the human placenta. The objective of the current review was to systematically screen the scientific literature using relevant keywords to collect quantitative data on placental transfer of these drugs in humans and to give an overview of current modeling approaches used in this context. The collected data encompassed clinically measured fetal:maternal (F:M) concentration ratios (ie, the ratio between drug concentrations measured in the umbilical cord and drug concentrations measured in the mother) and transfer data obtained from ex vivo cotyledon perfusion experiments. These data were found for 18 antidepressants and some of their pharmacologically active metabolites, and for 10 antipsychotics and the metabolites thereof. Based on the collected data, similar maternal and fetal exposure could be observed for only a few compounds (eg, Norfluoxetine and desvenlafaxine), whereas for most drugs (eg, paroxetine, sertraline, and quetiapine), fetal exposure appeared to be on average lower than maternal exposure. Venlafaxine appeared to be an exception in that the data indicated equivalent or higher concentrations in the umbilical cord than in the mother. Physiologically based pharmacokinetic (PBPK) models were sporadically used to investigate maternal pharmacokinetics of antidepressants or antipsychotics (eg, for sertraline, aripiprazole, and olanzapine), although without explicitly addressing fetal drug exposure. It is recommended that PBPK modeling is applied more frequently to these drugs. Although no substitute for clinical studies, these tools can help to better understand pregnancy-induced pharmacokinetic changes and ultimately contribute to a more evidence-based pharmacotherapy of depression and psychosis in pregnant subjects.
Prediction of Fluoxetine and Norfluoxetine Pharmacokinetic Profiles Using Physiologically Based Pharmacokinetic Modeling
J Clin Pharmacol 2021 Nov;61(11):1505-1513.PMID:34118174DOI:10.1002/jcph.1927.
Fluoxetine is a selective serotonin reuptake inhibitor that is metabolized to Norfluoxetine by cytochrome P450 (CYP) 2D6, CYP2C19, and CYP3A4. A physiologically based pharmacokinetic model for fluoxetine and Norfluoxetine metabolism was developed to predict and investigate changes in concentration-time profiles according to fluoxetine dosage in the Korean population. The model was developed based on the Certara repository model and information gleaned from the literature. Digitally extracted clinical study data were used to develop and verify the model. Simulations for plasma concentrations of fluoxetine and Norfluoxetine after a single dose of 60 or 80 mg fluoxetine were made based on 1000 virtual healthy Korean individuals using the SimCYP version 19 simulator. The mean ratios (simulated/observed) after a single administration of 80 mg fluoxetine for maximum plasma concentration, area under the plasma concentration-time curve, and apparent clearance were 1.12, 1.08, and 0.93 for fluoxetine; the ratios of maximum plasma concentration and area under the plasma concentration-time curve were 1.08 and 1.08, respectively, for Norfluoxetine, indicating that the simulated concentration-time profiles of fluoxetine and Norfluoxetine fitted the observed profiles well. The developed model was used to predict plasma fluoxetine and Norfluoxetine concentration-time profiles after repeated administrations of fluoxetine in Korean volunteers. This physiologically based pharmacokinetic model could provide basic understanding of the pharmacokinetic profiles of fluoxetine and its metabolite under various situations.
Assessing the Mechanism of Fluoxetine-Mediated CYP2D6 Inhibition
Pharmaceutics 2021 Jan 23;13(2):148.PMID:33498694DOI:10.3390/pharmaceutics13020148.
Fluoxetine is still one of the most widely used antidepressants in the world. The drug is extensively metabolized by several cytochrome P450 (CYP450) enzymes and subjected to a myriad of CYP450-mediated drug interactions. In a multidrug regimen, preemptive mitigation of drug-drug interactions requires knowledge of fluoxetine actions on these CYP450 enzymes. The major metabolic pathway of fluoxetine leading to the formation of its active metabolite, Norfluoxetine, is mediated by CYP2D6. Fluoxetine and Norfluoxetine are strong affinity substrates of CYP2D6 and can inhibit, potentially through various mechanisms, the metabolism of other sensitive CYP2D6 substrates. Remarkably, fluoxetine-mediated CYP2D6 inhibition subsides long after fluoxetine first passes through the liver and even remains long after the discontinuation of the drug. Herein, we review pharmacokinetic and pharmacogenetic information to help us understand the mechanisms underlying the prolonged inhibition of CYP2D6 following fluoxetine administration. We propose that long-term inhibition of CYP2D6 is likely a result of competitive inhibition. This is due to strong affinity binding of fluoxetine and Norfluoxetine to the enzyme and unbound fluoxetine and Norfluoxetine levels circulating in the blood for a long period of time because of their long elimination half-life. Additionally, we describe that fluoxetine is a CYP2C9 substrate and a mechanism-based inhibitor of CYP2C19.