BIBF 1202
目录号 : GC35516
An active metabolite of BIBF 1120
Cas No.:894783-71-2
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
BIBF 1202 is an active metabolite of the VEGFR, FGFR, and PDGFR inhibitor BIBF 1120 .1,2 It is formed from BIBF 1120 by intracellular esterases.1 BIBF 1202 inhibits VEGFR2 with an IC50 value of 62 nM.
1.Hilberg, F., Roth, G.J., Krssak, M., et al.BIBF 1120: Triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacyCancer Res.68(12)4774-4782(2008) 2.Lin, D., Qiao, L.M., Zhang, Y.N., et al.Simultaneous determination of nintedanib and its metabolite by UPLC-MS/MS in rat plasma and its application to a pharmacokinetic studyJ. Pharm. Biomed. Anal.117173-177(2016)
| Cas No. | 894783-71-2 | SDF | |
| Canonical SMILES | O=C(C1=CC(NC/2=O)=C(C=C1)C2=C(NC3=CC=C(N(C)C(CN4CCN(C)CC4)=O)C=C3)/C5=CC=CC=C5)O | ||
| 分子式 | C30H31N5O4 | 分子量 | 525.6 |
| 溶解度 | DMSO: ≥ 45 mg/mL (85.62 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 | 1.9026 mL | 9.5129 mL | 19.0259 mL |
| 5 mM | 0.3805 mL | 1.9026 mL | 3.8052 mL |
| 10 mM | 0.1903 mL | 0.9513 mL | 1.9026 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。
Pharmacokinetics and metabolism of BIBF 1120 after oral dosing to healthy male volunteers
Xenobiotica 2011 Apr;41(4):297-311.PMID:21204634DOI:10.3109/00498254.2010.545452.
The pharmacokinetics and metabolism of BIBF 1120, an oral triple angiokinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR), were studied in healthy male volunteers (n = 8) who had received a single oral dose of 100 mg [(14)C]-radiolabelled BIBF 1120 administered as solution. BIBF 1120 was well-tolerated and rapidly absorbed; median time to reach maximum plasma concentrations was 1.3 h and gMean terminal half-life was 13.7 h. A relatively high apparent total body clearance and volume of distribution possibly indicated a high tissue distribution. Plasma concentrations of BIBF 1120 plus carboxylate metabolite BIBF 1202 were lower than the total [(14)C]-radioactivity in plasma, indicating presence of additional metabolites. Total recovery in excreta was 94.7% 1 week post-dose; mass balance was considered complete after 96 h. BIBF 1120 and metabolites were mainly excreted via faeces. The major metabolic pathway for BIBF 1120 was methyl ester cleavage to BIBF 1202. Subsequently, the free carboxyl group of BIBF 1202 was glucuronidated to 1-O-acylglucuronide. Pathways of minor importance were oxidative N-demethylation to yield BIBF 1053, and oxidation of the piperazine moiety and conjugation. Glucuronidation of the parent drug and formylation of the secondary aliphatic amine of the piperazine ring played a minor role.
Simultaneous determination of nintedanib and its metabolite BIBF 1202 in different tissues of mice by UPLC-MS/MS and its application in drug tissue distribution study
J Chromatogr B Analyt Technol Biomed Life Sci 2015 Oct 1;1002:239-44.PMID:26342166DOI:10.1016/j.jchromb.2015.08.032.
A sensitive and rapid ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was developed to simultaneous determine nintedanib and BIBF 1202 in mice plasma and tissue using carbamazepine as the internal standard (IS). Sample preparation was accomplished through a protein precipitation procedure with acetonitrile. The analyte and IS were separated on an Acquity UPLC BEH C18 column (2.1mm×50mm, 1.7μm) with the mobile phase of acetonitrile and 0.1% formic acid in water with gradient elution at a flow rate of 0.40mL/min. The detection was performed on a triple quadrupole tandem mass spectrometer equipped with electrospray ionization (ESI) by multiple reactions monitoring (MRM) of the transitions at m/z 540.3→113.1 for nintedanib, m/z 526.3→113.1 for BIBF 1202 and m/z 237.1→194.1 for IS, respectively. The linearity of this method was found to be within the concentration range of 1-1000ng/mL with a lower limit of quantification of 1.0ng/mL for each drug. Only 3.0min was needed for an analytical run. The inter-day and intra-day precision and accuracy of quality control (QC) samples, evaluated both in plasma and tissue homogenates, were all within 15%. The method was successfully applied to the pharmacokinetic and tissue distribution study of nintedanib and BIBF 1202 in mice after oral administration of nintedanib.
Inhibition of human UDP-glucuronosyltransferase (UGT) enzymes by kinase inhibitors: Effects of dabrafenib, ibrutinib, nintedanib, trametinib and BIBF 1202
Biochem Pharmacol 2019 Nov;169:113616.PMID:31445021DOI:10.1016/j.bcp.2019.08.018.
We have demonstrated previously that the kinase inhibitors (KIs) lapatinib, pazopanib, regorafenib and sorafenib are potent inhibitors of UGT1A1 and UGTs 1A7-1A10. The present study characterised the effects of four additional drugs in this class, dabrafenib, ibrutinib, nintedanib and trametinib, on human UGT enzyme activities in vitro. Dabrafenib, ibrutinib, nintedanib and trametinib were potent inhibitors of human liver microsomal UGT1A1; Ki,u values ranged from 1.1 to 7.5 µM. Similarly, these KIs inhibited UGT 1A7, 1A8, 1A9 and 1A10, albeit less potently than UGT1A1. Despite the potent inhibition of UGT1A1, in vitro - in vivo extrapolation excluded the likelihood that dabrafenib, ibrutinib, nintedanib and trametinib would precipitate drug-drug interactions (DDIs) due to the low unbound plasma concentrations of these drugs observed in patients. The structures of dabrafenib, ibrutinib, lapatinib, nintedanib, pazopanib, regorafenib, trametinib and 22 other KIs overlaid well on that of sorafenib, a potent inhibitor of UGT1A1 and UGTs 1A7-1A10. Taken together, kinetic and computational modelling data suggest that all currently marketed KIs are likely to be potent inhibitors of UGT1A1, and are also likely to inhibit UGTs 1A7-1A10 to some extent due to the structural and chemical features shared in common by these drugs. By contrast, BIBF 1202, the major metabolite of nintedanib, did not appreciably inhibit human UGTs, due to the presence of a terminal electronegative group which appears to disfavor enzyme inhibition. Given the potent inhibition of several UGT enzymes, especially UGT1A1, by KIs, characterisation of the DDI potential of newly developed agents in this class is warranted.
Simultaneous determination of nintedanib and its metabolite by UPLC-MS/MS in rat plasma and its application to a pharmacokinetic study
J Pharm Biomed Anal 2016 Jan 5;117:173-7.PMID:26355771DOI:10.1016/j.jpba.2015.08.024.
To establish a rapid and sensitive ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for the determination of concentration of nintedanib and its metabolite BIBF 1202 in rat plasma. The nintedanib and its metabolite and the internal standard (diazepam) were separated on an Acquity UPLC BEH C18 chromatography column (2.1 mm×50 mm, 1.7 μm) using gradient elution with a mobile phase of acetonitrile and 0.1% formic acid in water at a flow rate of 0.30 mL/min. The detection was performed on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring (MRM) mode to monitor the precursor-to-product ion transitions of m/z540.3→113.1 for nintedanib, m/z526.3→113.0 for BIBF 1202 and m/z285.3→193.1 for diazepam (IS) using a positive electrospray ionization interface. The method was validated for 1.0-200 ng/mL for nintedanib and 0.5-100 ng/mL for BIBF 1202 using 100 μL of plasma sample. Total time for each chromatograph was 3.0 min. The intra- and inter-day precision and accuracy of the quality control samples at low, medium, and high concentration levels exhibited relative standard deviations (RSD) <10.8% and the accuracy values ranged from -11.9% to 10.4%. The method was successfully applied to a pharmacokinetic study of nintedanib and BIBF 1202 in rats after oral administration of nintedanib.
Population pharmacokinetics of nintedanib, an inhibitor of tyrosine kinases, in patients with non-small cell lung cancer or idiopathic pulmonary fibrosis
Cancer Chemother Pharmacol 2018 Jan;81(1):89-101.PMID:29119292DOI:10.1007/s00280-017-3452-0.
Purpose: A population pharmacokinetic model was developed for nintedanib in patients with non-small cell lung cancer (NSCLC) or idiopathic pulmonary fibrosis (IPF). The effects of intrinsic and extrinsic patient factors on exposure of nintedanib and its main metabolite BIBF 1202 were studied. Methods: Data from 1191 patients with NSCLC (n = 849) or IPF (n = 342) treated with oral nintedanib (once- or twice-daily, dose range 50-250 mg) in 4 Phase II or III studies were combined. Plasma concentrations of nintedanib (n = 5611) and BIBF 1202 (n = 5376) were analyzed using non-linear mixed-effects modeling. Results: Pharmacokinetics of nintedanib were described by a one-compartment model with linear elimination, first-order absorption, and absorption lag time. For a typical patient, the absorption rate was 0.0827 h-1, apparent total clearance was 897 L/h, apparent volume of distribution at steady state was 465 L, and lag time was 25 min. Age, weight, smoking, and Asian race were statistically significant covariates influencing nintedanib exposure, but no individual covariate at extreme values (5th and 95th percentiles of baseline values for continuous covariates) resulted in a change of more than 33% relative to a typical patient. Pharmacokinetics and covariate effects for BIBF 1202 were similar to nintedanib. Mild or moderate renal impairment and mild hepatic impairment (classified by transaminase or bilirubin increase above the upper limit of normal) or underlying disease had no significant effects on nintedanib pharmacokinetics. Conclusions: This model adequately described the pharmacokinetic profile of nintedanib in NSCLC and IPF populations and can be used for simulations exploring covariate effects and exposure-response analyses.