阿比特龙作用机制 - Medchemexpress - MCE中国

Product Data?SheetAbirateroneCat. No.:CAS No.:分?式:分?量:作?靶点:作?通路:储存?式:HY-70013154229-19-3C??H??NO349.51Cytochrome P450Metabolic Enzyme/ProteasePowderIn solvent-20°C4°C-80°C-20°C3 years2 years6 months1 monthInhibitors?Agonists?Screening Libraries溶解性数据体外实验DMF : 8.75 mg/mL (25.04 mM; Need ultrasonic and warming)Ethanol : 5.4 mg/mL (15.45 mM; Need ultrasonic)DMSO : 5 mg/mL (14.31 mM; Need ultrasonic)Mass1 mg5 mg10 mgSolventConcentration制备储备液1 mM5 mM10 mM2.8611 mL0.5722 mL0.2861 mL14.3057 mL2.8611 mL1.4306 mL28.6115 mL5.7223 mL2.8611 mL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；?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?式和期限：-80°C, 6 months; -20°C, 1 month。-80°C 储存时，请在 6 个?内使?，-20°C 储存时，请在 1 个?内使?。BIOLOGICAL ACTIVITY?物活性Abiraterone 是?种有效的不可逆的 CYP17A1 抑制剂，具有抗雄激素活性，抑制细胞?素 p450 酶 CYP17 的 17α-羟化酶和 17,20-裂合酶活性，IC50 值 分别为 2.5 nM 和 15 nM.IC?? & Target体外研究IC50:17α-hydroxylase (2.5 nM), 17,20-lyase (15 nM)[6]Significant inhibition of proliferation of the AR-positive prostate cancer cell lines LNCaP and VCaP with doses of Abiraterone ≥5 μM is confirmed[2]. Abiraterone shows IC50 values of 15 nM and 2.5 nM for the 17,20-lyase and 17α-hydroxylase (CYP17 is a bifunctional enzyme with both 17α-hydroxylase and 17,20-lyase activity). Abiraterone inhibits human 17,20-lyase and 17α-hydroxylase with IC50 of 27 and 30 nM respectively[3]. Abiraterone inhibits recombinant human 3βHSD1 and 3βHSD2 activity with competitive Ki values of 2.1 and 8.8 μM. 10 μM Abiraterone is sufficient to Page 1 of 2

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completely block synthesis of 5α-dione and DHT in both cell lines.Treatment with abi significantly inhibited CRPC progression in the robustly growing subset, effectively putting a ceiling on tumor growth over 4 weeks of treatment (P<0.00001). [3H]-dehydroepiandrosterone (DHEA) depletion and Δ4-androstenedione (AD) accumulation are inhibited by Abiraterone in LNCaP, with an IC50<1 μM[4].

体内研究

The 0.5 mmol/kg/d Abiraterone treatment dose is previously shown to yield serum concentrations of about 0.5 to 1 μM. Xenograft tumor growth in the control group is widely variable, with some tumors growing slowly and only a subset of tumors exhibiting robust growth[4]. Following i.v. administration (5 mg/kg) the clearance (Cl) and volume of distribution (Vd) are found to be 31.2 mL/min/kg and 1.97 L/kg, respectively. The AUC0-∞ (area under the plasma concentration-time curve from time zero to infinity time point) is found to be 2675 ng*h/mL. The terminal half-life (t

[5]

1/2) is 0.73 h. Because of high clearance, Abiraterone (ART) is quantifiable only until 2 h following i.v. administration.

PROTOCOL

Cell Assay [2]

LNCaP and VCaP cells are seeded in 96-well plates and grown in CSS-supplemented phenol red-free or FBS-supplemented media for 7 days. Cells are treated with Abiraterone (5 μM and 10 μM) at 24 and 96 hours after plating and cell viability is determined on day 7 by adding CellTiter Glo and measuring luminescence[2].MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Animal

Administration [4][5]

Mice[4]

Male NOD/SCID mice 6 to 8 weeks of age are surgically orchiectomized and implanted with a 5 mg 90-day sustained release DHEA pellet to mimic CRPC with human adrenal physiology. Two days later, 7×106 LAPC4 cells are injected subcutaneously with Matrigel. Tumor dimensions are measured 2 to 3 times per week, and volume is calculated as length×width×height×0.52. Once tumors reach 300 mm3, mice are randomly assigned to vehicle or Abiraterone treatment groups. Mice in the Abiraterone group are treated with 5 mL/kg intraperitoneal injections of 0.5

mmol/kg/d (0.1 mL 5% benzyl alcohol and 95% safflower oil solution) and control mice with vehicle only, once daily for 5 days per week over a duration of 4 weeks (n=8 mice per treatment). Statistical significance between Abiraterone and vehicle treatment groups is assessed by ANOVA based on a mixed-effect model. Rats[5]

Male Sprague-Dawley rats (n=8, 240-260 g) are used. Blood samples (450 μL) are obtained following an i.v. 5 mg/kg dose of ART into polypropylene tubes containing Na2-EDTA solution as an anticoagulant and at pre-dose, 0.12, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h (a sparse sampling protocol is adopted during blood collection and at each time point blood is collected from four animals). Plasma is harvested by centrifuging the blood using a Biofuge at 1760g for 5 min and stored frozen at -80±10°C until analysis.

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

客户使?本产品发表的科研?献

????Nature. 2012 Jan 22;482(7383):116-9.????Eur Urol. 2015 Aug;68(2):228-35.????Anal Chem. 2016 Oct 4;88(19):9347-9350.????Sci Rep. 2017 Mar 15;7:44409.????Acta Pharmacol Sin. 2020 May 12.

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REFERENCES

[1].?Attard G, et al. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol. 2008 Oct 1;26(28):4563-71.

[2].?Richards J, et al. Interactions of abiraterone, eplerenone, and prednisolone with wild-type and mutant androgen receptor: a rationale for increasing abiraterone exposure or combining with MDV3100. Cancer Res. 2012 May 1;72(9):2176-82.

[3].?Stein MN, et al. Androgen synthesis inhibitors in the treatment of castration-resistant prostate cancer. Asian J Androl. 2014 May-Jun;16(3):387-400.[4].?Li R, et al. Abiraterone inhibits 3β-hydroxysteroid dehydrogenase: a rationale for increasing drug exposure in castration-resistant prostate cancer. Clin Cancer Res. 2012 Jul 1;18(13):3571-9.

[5].?Kumar SV, et al. Validated RP-HPLC/UV method for the quantitation of abiraterone in rat plasma and its application to a pharmacokinetic study in rats. Biomed Chromatogr. 2013 Feb;27(2):203-7.

[6].?Stein MN, et al. Androgen synthesis inhibitors in the treatment of castration-resistant prostate cancer. Asian J Androl. 2014 May-Jun;16(3):387-400.

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