4-Hydroxyatomoxetine
(Synonyms: 4'-羟基托莫西汀) 目录号 : GC60517
A metabolite of atomoxetine
Cas No.:435293-66-6
Sample solution is provided at 25 µL, 10mM.
;)
,-1-7$$$37316672.jpg');)
;)
;)
$$$36806353.jpg');)
;33(7)%EF%BC%9A546-561$$$37156877.jpg');)
;)
;)
;)
%201124-1138.$$$35908550.jpg');)
%20766-780.$$$37100057.jpg');)
%20418-432.$$$36893736.jpg');)
%EF%BC%9A-240-255.$$$35108512.jpg');)
533-545$$$36543525.jpg');)
%201-13.$$$36600053.jpg');)
;)
Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
4-hydroxy Atomoxetine is a metabolite of the norepinephrine transporter (NET) inhibitor atomoxetine .1 It is formed from atomoxetine by the cytochrome P450 (CYP) isoform CYP2D6 in human liver microsomes.
1.Sauer, J.-M., Ring, B.J., and Witcher, J.W.Clinical pharmacokinetics of atomoxetineClin. Pharmacokinet.44(6)571-590(2005)
| Cas No. | 435293-66-6 | SDF | |
| 别名 | 4'-羟基托莫西汀 | ||
| Canonical SMILES | OC1=CC=C(O[C@@H](C2=CC=CC=C2)CCNC)C(C)=C1 | ||
| 分子式 | C17H21NO2 | 分子量 | 271.35 |
| 溶解度 | 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。 |
||
| 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 | |||
 |
1 mg | 5 mg | 10 mg |
| 1 mM | 3.6853 mL | 18.4264 mL | 36.8528 mL |
| 5 mM | 0.7371 mL | 3.6853 mL | 7.3706 mL |
| 10 mM | 0.3685 mL | 1.8426 mL | 3.6853 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。
The Effect of Myricetin on Pharmacokinetics of Atomoxetine and its Metabolite 4-Hydroxyatomoxetine In Vivo and In Vitro
Eur J Drug Metab Pharmacokinet 2017 Apr;42(2):261-268.PMID:27207674DOI:10.1007/s13318-016-0347-0.
Background and objectives: Atomoxetine is the first non-stimulant drug to be approved for the treatment of ADHD, while the effect of myricetin on the pharmacokinetic of atomoxetine in rats or human is still unknown. The present work was to study the impact of myricetin on the metabolism of atomoxetine both in vivo and in vitro. Methods: Twenty healthy male Sprague-Dawley rats were randomly divided into four groups: A (control group), B (100 mg/kg myricetin), C (50 mg/kg myricetin), and D (25 mg/kg myricetin). A single dose of atomoxetine (10 mg/kg) was administrated half an hour later. In addition, human and rat liver microsomes were performed to determine the effect of myricetin on the metabolism of atomoxetine in vitro. Results: Group B, C, D all increased the C max and AUC of atomoxetine, but decreased the C max and AUC of 4-Hydroxyatomoxetine. Moreover, myricetin showed inhibitory effect on human and rat microsomes, the IC50 of myricetin was 8.651 and 35.45 µmol/L, respectively. Conclusions: Our study showed that myricetin could significantly inhibit the formation of atomoxetine metabolite both in vivo and in vitro. It is recommended that the effect of myricetin on the metabolism of atomoxetine should be noted and atomoxetine plasma concentration should be monitored.
Clinical pharmacokinetics of atomoxetine
Clin Pharmacokinet 2005;44(6):571-90.PMID:15910008DOI:10.2165/00003088-200544060-00002.
Atomoxetine (Strattera, a potent and selective inhibitor of the presynaptic norepinephrine transporter, is used clinically for the treatment of attention-deficit hyperactivity disorder (ADHD) in children, adolescents and adults. Atomoxetine has high aqueous solubility and biological membrane permeability that facilitates its rapid and complete absorption after oral administration. Absolute oral bioavailability ranges from 63 to 94%, which is governed by the extent of its first-pass metabolism. Three oxidative metabolic pathways are involved in the systemic clearance of atomoxetine: aromatic ring-hydroxylation, benzylic hydroxylation and N-demethylation. Aromatic ring-hydroxylation results in the formation of the primary oxidative metabolite of atomoxetine, 4-Hydroxyatomoxetine, which is subsequently glucuronidated and excreted in urine. The formation of 4-Hydroxyatomoxetine is primarily mediated by the polymorphically expressed enzyme cytochrome P450 (CYP) 2D6. This results in two distinct populations of individuals: those exhibiting active metabolic capabilities (CYP2D6 extensive metabolisers) and those exhibiting poor metabolic capabilities (CYP2D6 poor metabolisers) for atomoxetine. The oral bioavailability and clearance of atomoxetine are influenced by the activity of CYP2D6; nonetheless, plasma pharmacokinetic parameters are predictable in extensive and poor metaboliser patients. After single oral dose, atomoxetine reaches maximum plasma concentration within about 1-2 hours of administration. In extensive metabolisers, atomoxetine has a plasma half-life of 5.2 hours, while in poor metabolisers, atomoxetine has a plasma half-life of 21.6 hours. The systemic plasma clearance of atomoxetine is 0.35 and 0.03 L/h/kg in extensive and poor metabolisers, respectively. Correspondingly, the average steady-state plasma concentrations are approximately 10-fold higher in poor metabolisers compared with extensive metabolisers. Upon multiple dosing there is plasma accumulation of atomoxetine in poor metabolisers, but very little accumulation in extensive metabolisers. The volume of distribution is 0.85 L/kg, indicating that atomoxetine is distributed in total body water in both extensive and poor metabolisers. Atomoxetine is highly bound to plasma albumin (approximately 99% bound in plasma). Although steady-state concentrations of atomoxetine in poor metabolisers are higher than those in extensive metabolisers following administration of the same mg/kg/day dosage, the frequency and severity of adverse events are similar regardless of CYP2D6 phenotype.Atomoxetine administration does not inhibit or induce the clearance of other drugs metabolised by CYP enzymes. In extensive metabolisers, potent and selective CYP2D6 inhibitors reduce atomoxetine clearance; however, administration of CYP inhibitors to poor metabolisers has no effect on the steady-state plasma concentrations of atomoxetine.
Identification of the human cytochromes P450 responsible for atomoxetine metabolism
Drug Metab Dispos 2002 Mar;30(3):319-23.PMID:11854152DOI:10.1124/dmd.30.3.319.
Studies were performed to determine the human enzymes responsible for the biotransformation of atomoxetine to its major metabolite, 4-Hydroxyatomoxetine, and to a minor metabolite, N-desmethylatomoxetine. Utilizing human liver microsomes containing a full complement of cytochrome P450 (P450) enzymes, average K(m) and CL(int) values of 2.3 microM and 103 microl/min/mg, respectively, were obtained for 4-Hydroxyatomoxetine formation. Microsomal samples deficient in CYP2D6 exhibited average apparent K(m) and CL(int) values of 149 microM and 0.2 microl/min/mg, respectively. In a human liver bank characterized for P450 content, formation of 4-Hydroxyatomoxetine correlated only to CYP2D6 activity. Of nine expressed P450s examined, 4-Hydroxyatomoxetine was formed at a rate 475-fold greater by CYP2D6 compared with the other P450s. These results demonstrate that CYP2D6 is the enzyme primarily responsible for the formation of 4-Hydroxyatomoxetine. Multiple P450s were found to be capable of forming 4-Hydroxyatomoxetine when CYP2D6 was not expressed. However, the efficiency at which these enzymes perform this biotransformation is reduced compared with CYP2D6. The formation of the minor metabolite N-desmethylatomoxetine exhibited average K(m) and CL(int) values of 83 microM and 0.8 microl/min/mg, respectively. Utilizing studies similar to those outlined above, CYP2C19 was identified as the primary enzyme responsible for the biotransformation of atomoxetine to N-desmethylatomoxetine. In summary, CYP2D6 was found to be the primary P450 responsible for the formation of the major oxidative metabolite of atomoxetine, 4-Hydroxyatomoxetine. Furthermore, these studies indicate that in patients with compromised CYP2D6 activity, multiple low-affinity enzymes will participate in the formation of 4-Hydroxyatomoxetine. Therefore, coadministration of P450 inhibitors to poor metabolizers of CYP2D6 substrates would not be predicted to decrease the clearance of atomoxetine in these individuals.
Effects of paroxetine on the pharmacokinetics of atomoxetine and its metabolites in different CYP2D6 genotypes
Arch Pharm Res 2020 Dec;43(12):1356-1363.PMID:33245517DOI:10.1007/s12272-020-01300-8.
The aim of this study was to investigate the effects of paroxetine, a potent inhibitor of CYP2D6, on the pharmacokinetics of atomoxetine and its two metabolites, 4-Hydroxyatomoxetine and N-desmethylatomoxetine, in different CYP2D6 genotypes. Twenty-six healthy subjects were recruited and divided into CYP2D6*wt/*wt (*wt=*1 or *2, n = 10), CYP2D6*wt/*10 (n = 9), and CYP2D6*10/*10 groups (n = 7). In atomoxetine phase, all subjects received a single oral dose of atomoxetine (20 mg). In paroxetine phase, after administration of a single oral dose of paroxetine (20 mg) for six consecutive days, all subjects received a single oral dose of atomoxetine with paroxetine. Plasma concentrations of atomoxetine and its metabolites were determined up to 24 h after dosing. During atomoxetine phase, there were significant differences in Cmax and AUC0-24 of atomoxetine and N-desmethylatomoxetine among three genotype groups, whereas significant differences were not found in relation to CYP2D6*10 allele after administration of paroxetine. AUC ratios of 4-Hydroxyatomoxetine and N-desmethylatomoxetine to atomoxetine were significantly different among three genotype groups during atomoxetine phase (all, P < 0.001), but after paroxetine treatment significant differences were not found. After paroxetine treatment, AUC0-24 of atomoxetine was increased by 2.3-, 1.7-, and 1.3-fold, in CYP2D6*wt/*wt, CYP2D6*wt/*10, and CYP2D6*10/*10 groups in comparison to atomoxetine phase, respectively. AUC ratio of 4-Hydroxyatomoxetine to atomoxetine in each group was significantly decreased, whereas AUC ratio of N-desmethylatomoxetine to atomoxetine significantly increased after administration of paroxetine. In conclusion, paroxetine coadministration significantly affected pharmacokinetic parameters of atomoxetine and its two metabolites, 4-Hydroxyatomoxetine and N-desmethylatomoxetine. When atomoxetine was administered alone, Cmax, AUC0-24 and CL/F of atomoxetine were significantly different among the three CYP2D6 genotype groups. However, after paroxetine coadministration, no significant differences in these pharmacokinetic parameters were observed among the CYP2D6 genotype groups.
Simple pharmacokinetic models accounting for drug monitoring results of atomoxetine and its 4-hydroxylated metabolites in Japanese pediatric patients genotyped for cytochrome P450 2D6
Drug Metab Pharmacokinet 2020 Apr;35(2):191-200.PMID:32184039DOI:10.1016/j.dmpk.2019.08.005.
Atomoxetine is an approved medicine for attention-deficit/hyperactivity disorder and a cytochrome P450 2D6 (CYP2D6) probe substrate. Simple physiologically based pharmacokinetic (PBPK) models and compartment models were set up to account for drug monitoring results of 33 Japanese patients (6-15 years of age) to help establish the correct dosage for the evaluation of clinical outcomes. The steady-state one-point drug monitoring data for the most participants indicated the extensive biotransformation of atomoxetine to 4-Hydroxyatomoxetine under individually prescribed doses of atomoxetine. However, 5 participants (with impaired CYP2D6 activity scores based on the CYP2D6 genotypes) showed high plasma concentrations of atomoxetine (0.53-1.5 μM) compared with those of total 4-Hydroxyatomoxetine (0.49-1.4 μM). Results from full PBPK models using the in-built Japanese pediatric system of software Simcyp, one-compartment models, and new simple PBPK models (using parameters that reflected the subjects' small body size and normal/reduced CYP2D6-dependent clearance) could overlay one-point measured drug/metabolite plasma concentrations from almost common 28 participants within threefold ranges. Validated one-compartment or simple PBPK models can be used to predict steady-state plasma concentrations of atomoxetine and/or its primary metabolites in Japanese pediatric patients (>6 years) who took a variety of individualized doses in a clinical setting.