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Axitinib Sulfoxide Sale

(Synonyms: 阿西替尼杂质A) 目录号 : GC42887

A major inactive metabolite of axitinib

Axitinib Sulfoxide Chemical Structure

Cas No.:1347304-18-0

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1mg
¥839.00
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5mg
¥2,947.00
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Sample solution is provided at 25 µL, 10mM.

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产品描述

Axitinib sulfoxide is a major inactive metabolite of the tyrosine kinase inhibitor axitinib . It is formed from axitinib primarily by the cytochrome P450 (CYP) isoform CYP3A4 with minor contributions from CYP3A5 and CYP2C19.

Chemical Properties

Cas No. 1347304-18-0 SDF
别名 阿西替尼杂质A
Canonical SMILES O=C(NC)C1=C(S(C2=CC3=C(C(/C=C/C4=NC=CC=C4)=NN3)C=C2)=O)C=CC=C1
分子式 C22H18N4O2S 分子量 402.5
溶解度 Soluble in DMSO 储存条件 Store at -20°C
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溶解性数据

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1 mg 5 mg 10 mg
1 mM 2.4845 mL 12.4224 mL 24.8447 mL
5 mM 0.4969 mL 2.4845 mL 4.9689 mL
10 mM 0.2484 mL 1.2422 mL 2.4845 mL
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Research Update

In Vitro Kinetic Characterization of Axitinib Metabolism

Drug Metab Dispos 2016 Jan;44(1):102-14.PMID:26512042DOI:10.1124/dmd.115.065615.

N-Methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamide (axitinib) is an oral inhibitor of vascular endothelial growth factor receptors 1-3, which is approved for the treatment of advanced renal cell cancer. Human [(14)C]-labeled clinical studies indicate axitinib's primary route of clearance is metabolism. The aims of the in vitro experiments presented herein were to identify and characterize the enzymes involved in axitinib metabolic clearance. In vitro biotransformation studies of axitinib identified a number of metabolites including an Axitinib Sulfoxide, several less abundant oxidative metabolites, and glucuronide conjugates. The most abundant NADPH- and UDPGA-dependent metabolites, Axitinib Sulfoxide (M12) and axitinib N-glucuronide (M7) were selected for phenotyping and kinetic study. Phenotyping experiments with human liver microsomes (HLMs) using chemical inhibitors and recombinant human cytochrome P450s demonstrated axitinib was predominately metabolized by CYP3A4/5, with minor contributions from CYP2C19 and CYP1A2. The apparent substrate concentration at half-maximal velocity (Km) and Vmax values for the formation of Axitinib Sulfoxide by CYP3A4 or CYP3A5 were 4.0 or 1.9 µM and 9.6 or 1.4 pmol·min(-1)·pmol(-1), respectively. Using a CYP3A4-specific inhibitor (Cyp3cide) in liver microsomes expressing CYP3A5, 66% of the axitinib intrinsic clearance was attributable to CYP3A4 and 15% to CYP3A5. Axitinib N-glucuronidation was primarily catalyzed by UDP-glucuronosyltransferase (UGT) UGT1A1, which was verified by chemical inhibitors and UGT1A1 null expressers, with lesser contributions from UGTs 1A3, 1A9, and 1A4. The Km and Vmax values describing the formation of the N-glucuronide in HLM or rUGT1A1 were 2.7 µM or 0.75 µM and 8.9 or 8.3 pmol·min(-1)·mg(-1), respectively. In summary, CYP3A4 is the major enzyme involved in axitinib clearance with lesser contributions from CYP3A5, CYP2C19, CYP1A2, and UGT1A1.

Pharmacokinetics, metabolism, and excretion of [14C]axitinib, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, in humans

Drug Metab Dispos 2014 May;42(5):918-31.PMID:24608633DOI:10.1124/dmd.113.056531.

The disposition of a single oral dose of 5 mg (100 μCi) of [(14)C]axitinib was investigated in fasted healthy human subjects (N = 8). Axitinib was rapidly absorbed, with a median plasma Tmax of 2.2 hours and a geometric mean Cmax and half-life of 29.2 ng/ml and 10.6 hours, respectively. The plasma total radioactivity-time profile was similar to that of axitinib but the AUC was greater, suggesting the presence of metabolites. The major metabolites in human plasma (0-12 hours), identified as axitinib N-glucuronide (M7) and Axitinib Sulfoxide (M12), were pharmacologically inactive, and with axitinib comprised 50.4%, 16.2%, and 22.5% of the radioactivity, respectively. In excreta, the majority of radioactivity was recovered in most subjects by 48 hours postdose. The median radioactivity excreted in urine, feces, and total recovery was 22.7%, 37.0%, and 59.7%, respectively. The recovery from feces was variable across subjects (range, 2.5%-60.2%). The metabolites identified in urine were M5 (carboxylic acid), M12 (sulfoxide), M7 (N-glucuronide), M9 (sulfoxide/N-oxide), and M8a (methylhydroxy glucuronide), accounting for 5.7%, 3.5%, 2.6%, 1.7%, and 1.3% of the dose, respectively. The drug-related products identified in feces were unchanged axitinib, M14/15 (mono-oxidation/sulfone), M12a (epoxide), and an unidentified metabolite, comprising 12%, 5.7%, 5.1%, and 5.0% of the dose, respectively. The proposed mechanism to form M5 involved a carbon-carbon bond cleavage via M12a, followed by rearrangement to a ketone intermediate and subsequent Baeyer-Villiger rearrangement, possibly through a peroxide intermediate. In summary, the study characterized axitinib metabolites in circulation and primary elimination pathways of the drug, which were mainly oxidative in nature.