N-Desmethyl imatinib
(Synonyms: N-去甲基伊马替尼; Norimatinib; Imatinib metabolite N-Desmethyl imatinib) 目录号 : GC33495
A major active metabolite of imatinib
Cas No.:404844-02-6
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
N-desmethyl Imatinib is a major active metabolite of imatinib , an anticancer agent that selectively targets tyrosine kinases, including Bcr-ABL, platelet-derived growth factor receptor (PDGFR), and KIT.1,2 N-desmethyl Imatinib is formed when imatinib undergoes demethylation by the cytochrome P450 (CYP) isomer CYP3A4.3 N-desmethyl Imatinib has the same in vitro potency at Bcr-ABL kinase as imatinib (IC50 = 38 nM for both) but is only present in plasma at 10-15% of the levels of imatinib, indicating the majority of the anticancer activity can be attributed to the parent compound.
1.Druker, B.J.Translation of the Philadelphia chromosome into therapy for CMLBlood112(13)4808-4817(2008) 2.Müller, B.A.Imatinib and its successors-how modern chemistry has changed drug developmentCurr. Pharm. Des.15(2)120-133(2009) 3.Obach, R.S.Pharmacologically active drug metabolites: Impact on drug discovery and pharmacotherapyPharmacol. Rev.65(2)578-640(2013)
| Cas No. | 404844-02-6 | SDF | |
| 别名 | N-去甲基伊马替尼; Norimatinib; Imatinib metabolite N-Desmethyl imatinib | ||
| Canonical SMILES | O=C(NC1=CC=C(C)C(NC2=NC(C3=CC=CN=C3)=CC=N2)=C1)C4=CC=C(CN5CCNCC5)C=C4 | ||
| 分子式 | C28H29N7O | 分子量 | 479.58 |
| 溶解度 | DMSO : ≥ 31 mg/mL (64.64 mM) | 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 | 2.0852 mL | 10.4258 mL | 20.8516 mL |
| 5 mM | 0.417 mL | 2.0852 mL | 4.1703 mL |
| 10 mM | 0.2085 mL | 1.0426 mL | 2.0852 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。
Method development for determination of imatinib and its major metabolite, N-Desmethyl imatinib, in biological and environmental samples by SA-SHS-LPME and HPLC
Biomed Chromatogr 2021 Jul;35(7):e5088.PMID:33590534DOI:10.1002/bmc.5088.
A salting-out-assisted switchable hydrophilicity solvent-based liquid phase microextraction (SA-SHS-LPME) was developed for the separation and determination of trace amounts of imatinib and N-Desmethyl imatinib in biological and environmental samples by HPLC-UV. Triethylamine as a hydrophobic compound and protonated triethylamine carbonate as a hydrophilic one were switched by the addition or elimination of CO2 . The use of NaOH resulted in the elimination of CO2 from the sample solution, which led to the conversion of P-TEA-C into triethylamine (TEA) and as a result, the analytes was extracted and entered the TEA phase. The salting out was performed to speed up the formation of the TEA in the shape of fine droplets in the specimen solution. Furthermore, the impact of several momentous factors that influence the recovery of the extraction was investigated. Under the optimum conditions, the limit of detection and limit of quantification were obtained in ranges of 0.03-0.05 and 0.1-0.15 μg L-1 for imatinib and 0.04-0.06 and 0.13-0.20 μg L-1 for N-Desmethyl imatinib, respectively. The preconcentration factor was 250. Inter- and intraday precision (RSD, n = 5) was <5%. In the case of imatinib and N-Desmethyl imatinib in biological and environmental specimens, a range of 97.0-102% was obtained as the recovery.
The effect of grape seed and green tea extracts on the pharmacokinetics of imatinib and its main metabolite, N-Desmethyl imatinib, in rats
BMC Pharmacol Toxicol 2020 Nov 16;21(1):77.PMID:33198812DOI:10.1186/s40360-020-00456-9.
Background: Imatinib is mainly metabolized by CYP3A4 and to a lesser extent by other isoenzymes, with N-Desmethyl imatinib being its major equipotent metabolite. Being a CYP3A4 substrate, imatinib co-administration with CYP3A4 modulators would change its pharmacokinetic profile. The cancer chemoprevention potential and anticancer efficacy of many herbal products such as grape seed (GS) and green tea (GT) extracts had led to an increase in their concomitant use with anticancer agents. GS and GT extracts were demonstrated to be potent inhibitors of CYP3A4. The aim of this study is to investigate the effect of standardized GS and/or GT extracts at two different doses on the pharmacokinetics of imatinib and its metabolite, N-Desmethyl imatinib, in SD-rats. Methods: Standardized GS and/or GT extracts were administered orally once daily for 21 days, at low (l) and high (h) doses, 50 and 100 mg/kg, respectively, before the administration of a single intragastric dose of imatinib. Plasma samples were collected and analyzed for imatinib and N-Desmethyl imatinib concentrations using LC-MS/MS method, then their non-compartmental pharmacokinetic parameters were determined. Results: h-GS dose significantly decreased imatinib's Cmax and the [Formula: see text] by 61.1 and 72.2%, respectively. Similar effects on N-Desmethyl imatinib's exposure were observed as well, in addition to a significant increase in its clearance by 3.7-fold. l-GT caused a significant decrease in imatinib's Cmax and [Formula: see text] by 53.6 and 63.5%, respectively, with more significant effects on N-Desmethyl imatinib's exposure, which exhibited a significant decrease by 79.2 and 81.1%, respectively. h-GT showed similar effects as those of l-GT on the kinetics of imatinib and its metabolite. However, when these extracts were co-administered at low doses, no significant effects were shown on the pharmacokinetics of imatinib and its metabolite. Nevertheless, increasing the dose caused a significant decrease in Cmax of N-Desmethyl imatinib by 71.5%. Conclusions: These results demonstrated that the pharmacokinetics of imatinib and N-Desmethyl imatinib had been significantly affected by GS and/or GT extracts, which could be partially explained by the inhibition of CYP3A-mediated metabolism. However, the involvement of other kinetic pathways such as other isoenzymes, efflux and uptake transporters could be involved and should be characterized.
Impact of CYP2C8*3 polymorphism on in vitro metabolism of imatinib to N-Desmethyl imatinib
Xenobiotica 2016;46(3):278-87.PMID:26161459DOI:10.3109/00498254.2015.1060649.
1. Imatinib is metabolized to N-Desmethyl imatinib by CYPs 3A4 and 2C8. The effect of CYP2C8*3 genotype on N-Desmethyl imatinib formation was unknown. 2. We examined imatinib N-demethylation in human liver microsomes (HLMs) genotyped for CYP2C8*3, in CYP2C8*3/*3 pooled HLMs and in recombinant CYP2C8 and CYP3A4 enzymes. Effects of CYP-selective inhibitors on N-demethylation were also determined. 3. A single-enzyme Michaelis-Menten model with autoinhibition best fitted CYP2C8*1/*1 HLM (n = 5) and recombinant CYP2C8 kinetic data (median ± SD Ki = 139 ± 61 µM and 149 µM, respectively). Recombinant CYP3A4 showed two-site enzyme kinetics with no autoinhibition. Three of four CYP2C8*1/*3 HLMs showed single-enzyme kinetics with no autoinhibition. Binding affinity was higher in CYP2C8*1/*3 than CYP2C8*1/*1 HLM (median ± SD Km = 6 ± 2 versus 11 ± 2 µM, P=0.04). CYP2C8*3/*3 (pooled HLM) also showed high binding affinity (Km = 4 µM) and single-enzyme weak autoinhibition (Ki = 449 µM) kinetics. CYP2C8 inhibitors reduced HLM N-demethylation by 47-75%, compared to 0-30% for CYP3A4 inhibitors. 4. In conclusion, CYP2C8*3 is a gain-of-function polymorphism for imatinib N-demethylation, which appears to be mainly mediated by CYP2C8 and not CYP3A4 in vitro in HLM.
LC-MS-MS determination of imatinib and N-Desmethyl imatinib in human plasma
J Chromatogr Sci 2014 Apr;52(4):344-50.PMID:23574742DOI:10.1093/chromsci/bmt037.
A specific and sensitive liquid chromatography-electrospray ionization-tandem mass spectrometric method was developed for the quantification of imatinib and its primary metabolite N-Desmethyl imatinib in human plasma. Protein precipitation with methanol was used for sample preparation. High-performance liquid chromatographic separation was performed on a Thermo BDS Hypersil C18 column (4.6 × 100 mm, 2.4 µm) with methanol-water (55:45, v/v) containing 0.1% formic acid and 0.2% ammonium acetate as the mobile phase, using isocratic elution at a flow rate of 0.7 mL/min. Detection was conducted with positive electrospray ionization multiple reaction monitoring of the ion transitions at m/z 494 → 394 for imatinib, 480 → 394 for N-Desmethyl imatinib and 297 → 110 for the internal standard (palonosetron). The assay was validated in the concentration ranges of 8-5,000 ng/mL for imatinib and 3-700 ng/mL for N-Desmethyl imatinib. The quantification limits for imatinib and N-Desmethyl imatinib were 8 and 3 ng/mL, respectively. The intra-day and inter-day precision values of the assay (expressed as percentage relative standard deviation) were less than 15% at all concentration levels within the tested range, and the accuracy values were between 85 and 115%. The established method was successfully applied to the pharmacokinetic study of imatinib mesylate capsules in 24 healthy Chinese volunteers.
Determination of unbound fraction of imatinib and N-Desmethyl imatinib, validation of an UPLC-MS/MS assay and ultrafiltration method
J Chromatogr B Analyt Technol Biomed Life Sci 2012 Oct 15;907:94-100.PMID:23000741DOI:10.1016/j.jchromb.2012.09.007.
Imatinib is a small-molecule tyrosine kinase inhibitor with large inter-individual but low intra-individual pharmacokinetic variability with consistent concentration-efficacy and concentration-toxicity relationships. For these reasons imatinib therapeutic drug monitoring is based on total plasma concentrations. However, since a significant impact of unbound imatinib concentrations on clinical response and/or toxicity evaluation has been suggested, the quantification of free fraction of imatinib and its active metabolite are of interest for therapeutic monitoring. Hence a reliable method for both separation and assay of the free fraction is needed. Using plasma samples spiked with imatinib (from 1000 to 7500 ng/mL) and its metabolite (from 1000 to 2500 ng/mL), an ultrafiltration procedure and an UPLC assay which give reproductive values for unbound fractions of imatinib (mean 3.0±1.0%) and metabolite N-Desmethyl imatinib (3.6±1.8%) have been developed. The validation of the analytical UPLC-MS/MS method associated to ultrafiltration for quantification of imatinib and N-Desmethyl imatinib was reported. The LOQ was set at 10 ng/mL for imatinib and 20 ng/mL for N-Desmethyl imatinib, intraday CV (%) ranged from 2.7 to 4.8% for imatinib and from 5.4 to 12.4% for N-Desmethyl imatinib and interday CV (%) ranged from 5.6 to 6.5% for imatinib and from 5.4 to 16.1% for N-Desmethyl imatinib. Methodological modifications were attempted to overcome non specific binding (NSB) on the ultrafiltration device. Two types of devices previously used for unbound determination of drugs were tested. Our results clearly showed that the methodology and the features of devices used for ultrafiltration could totally compromise the determination of unbound concentrations of a drug.