Voriconazole
(Synonyms: 伏立康唑,(±)-UK-109496) 目录号 : GC13079
Voriconazole是一种强效竞争性抑制剂，可抑制CYP2B6（IC50=1.71μM）、CYP2C9（IC50=3.62μM）、CYP2C19（IC50=5.25μM）和CYP3A（IC50=2.90μM）。
Cas No.:137234-62-9
Sample solution is provided at 25 µL, 10mM.
Voriconazole is a potent competitive inhibitor of CYP2B6 (IC50=1.71μM), CYP2C9 (IC50=3.62μM), CYP2C19 (IC50=5.25μM), and CYP3A (IC50=2.90μM)[1]. Voriconazole inhibited AfCYP51A and AfCYP51B activities in recombinant Aspergillus fumigatus with IC50 values of 0.38µM and 0.33µM, respectively, leading to inhibition of ergosterol biosynthesis[2]. Voriconazole has potent activity against a variety of clinically important fungal pathogens, including Aspergillus, Candida, Cryptococcus neoformans, and some less common moulds[3].
In vitro, Voriconazole treatment for 48h significantly inhibited 102 clinical Candida species and Saccharomyces cerevisiae isolates with MIC50≤0.125µg/mL[4]. At a concentration of 1000μg/ml, Voriconazole significantly reduced the cell viability of human corneal endothelial cells, altered the morphological characteristics, and significantly activated the apoptotic pathway[5]. At a concentration of 135μM, Voriconazole treatment for 7 days in primary human keratinocytes (PHK) upregulated genes related to cell division, chromosome condensation, DNA replication, spindle organization, and cell cycle checkpoint control, and downregulated genes related to terminal epithelial differentiation and protease inhibitor activity[6].
In vivo, Voriconazole treatment via intravenous administration (40mg/kg plus grapefruit gavage twice daily) for 7 days, the renal and brain burdens of mice infected with Candida tropicalis were alleviated[7]. Oral administration of Voriconazole (40mg/kg) daily for 21 days significantly reduced the fungal burden in the lungs of BALB/cByJ mice, increased the survival rate, and alleviated murine pulmonary blastomycosis[8].
References:
[1] Jeong S, Nguyen P D, Desta Z. Comprehensive in vitro analysis of voriconazole inhibition of eight cytochrome P450 (CYP) enzymes: major effect on CYPs 2B6, 2C9, 2C19, and 3A[J]. Antimicrobial agents and chemotherapy, 2009, 53(2): 541-551.
[2] Warrilow A G S, Parker J E, Price C L, et al. Isavuconazole and voriconazole inhibition of sterol 14α-demethylases (CYP51) from Aspergillus fumigatus and Homo sapiens[J]. International Journal of Antimicrobial Agents, 2019, 54(4): 449-455.
[3] Theuretzbacher U, Ihle F, Derendorf H. Pharmacokinetic/pharmacodynamic profile of voriconazole[J]. Clinical pharmacokinetics, 2006, 45(7): 649-663.
[4] Chryssanthou E, Cuenca-Estrella M. Comparison of the Antifungal Susceptibility Testing Subcommittee of the European Committee on Antibiotic Susceptibility Testing proposed standard and the E-test with the NCCLS broth microdilution method for voriconazole and caspofungin susceptibility testing of yeast species[J]. Journal of clinical microbiology, 2002, 40(10): 3841-3844.
[5] Han S B, Shin Y J, Hyon J Y, et al. Cytotoxicity of voriconazole on cultured human corneal endothelial cells[J]. Antimicrobial Agents and Chemotherapy, 2011, 55(10): 4519-4523.
[6] Mansh M, Ing L, Dimon M, et al. Voriconazole exposure regulates distinct cell‐cycle and terminal differentiation pathways in primary human keratinocytes[J]. British Journal of Dermatology, 2017, 176(3): 816-820.
[7] Majithiya J, Sharp A, Parmar A, et al. Efficacy of isavuconazole, voriconazole and fluconazole in temporarily neutropenic murine models of disseminated Candida tropicalis and Candida krusei[J]. Journal of Antimicrobial Chemotherapy, 2009, 63(1): 161-166.
[8] Sugar A M, Liu X P. Efficacy of voriconazole in treatment of murine pulmonary blastomycosis[J]. Antimicrobial agents and chemotherapy, 2001, 45(2): 601-604.
Voriconazole是一种强效竞争性抑制剂，可抑制CYP2B6（IC50=1.71μM）、CYP2C9（IC50=3.62μM）、CYP2C19（IC50=5.25μM）和CYP3A（IC50=2.90μM）[1]。Voriconazole能抑制重组烟曲霉中的AfCYP51A和AfCYP51B活性（IC50值分别为0.38µM和0.33µM），阻断麦角固醇生物合成[2]。Voriconazole对多种临床重要真菌病原体（包括曲霉、念珠菌、新型隐球菌及部分罕见霉菌）均具有强效活性[3]。
在体外，Voriconazole处理48小时可显著抑制102种临床念珠菌属和酿酒酵母分离株（MIC50≤0.125µg/mL）[4]。1000μg/ml浓度的Voriconazole会显著降低人角膜内皮细胞活力，改变细胞形态特征并激活凋亡通路[5]。135μM的Voriconazole处理原代人角质形成细胞（PHK）7天，可上调细胞分裂、染色体凝集、DNA复制、纺锤体组织和细胞周期检查点控制相关基因，同时下调终末上皮分化和蛋白酶抑制剂活性相关基因[6]。
在体内，静脉注射Voriconazole（40mg/kg联合葡萄柚灌胃，每日两次，持续7天）后，感染热带念珠菌的小鼠肾脏和脑部真菌负荷减轻[7]。BALB/cByJ小鼠每日口服Voriconazole（40mg/kg，持续21天）可显著降低肺部真菌负荷，提高生存率并缓解肺芽生菌病[8]。
| Cell experiment [1]: | |
Cell lines | Human corneal endothelial cells |
Preparation Method | Human corneal endothelial cells (5 ×104 cells/ml) were grown in 96-well plates for 48 hours and treated with different concentrations (0, 5, 25, 50, 100, 250, 500, and 1000μg/ml) of Voriconazole. After 24 hours, human corneal endothelial cells were washed and the degree of cell growth was evaluated using CCK-8 assay, absorbance at 450nm was measured using a microplate reader. |
Reaction Conditions | 0, 5, 25, 50, 100, 250, 500, and 1000μg/ml; 24h |
Applications | Voriconazole treatment significantly inhibited the cell viability at the concentration ≥ 100μg/ml. |
| Animal experiment [2]: | |
Animal models | BALB/cByJ mice |
Preparation Method | Male BALB/cByJ mice were allowed to freely consume mouse food and water. Five days before infection, the water in the water bottles was replaced with grapefruit juice and the mice were allowed to drink freely. The mice consumed an average of 2 to 3ml of grapefruit juice per day. The mice were lightly anesthetized with fentanyl. Approximately 5 × 104 CFU of B. dermatitidis yeasts/0.05ml solution was placed in the nostrils of the mice, and the mice remained in a standing position. After inhaling the droplets, the mice were returned to the cage. Ten mice were used in each group for survival rate determination. Voriconazole treatment was initiated 5 days after infection and continued for 21 days. Voriconazole was administered orally by gavage at a dose of 40mg/kg/day. The mice were observed twice a day, and the death situation was recorded. The experiment ended on the 45th day, and the mice were sacrificed, the lungs were removed and homogenized for processing. The cultures were inoculated on glucose agar plates at an appropriate dilution and incubated at 37°C for 5 days before counting the colony numbers. |
Dosage form | 40mg/kg/day for 21 days; p.o. |
Applications | Voriconazole treatment increased the survival rate of mice and reduced the fungal burden in the lungs. |
References: | |
| Cas No. | 137234-62-9 | SDF | |
| 别名 | 伏立康唑,(±)-UK-109496 | ||
| 化学名 | (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1,2,4-triazol-1-yl)butan-2-ol | ||
| Canonical SMILES | CC(C1=NC=NC=C1F)C(CN2C=NC=N2)(C3=C(C=C(C=C3)F)F)O | ||
| 分子式 | C16H14F3N5O | 分子量 | 349.31 |
| 溶解度 | ≥ 34.9 mg/mL in DMSO, ≥ 45 mg/mL in EtOH with ultrasonic and warming | 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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1 mg | 5 mg | 10 mg |
| 1 mM | 2.8628 mL | 14.3139 mL | 28.6279 mL |
| 5 mM | 572.6 μL | 2.8628 mL | 5.7256 mL |
| 10 mM | 286.3 μL | 1.4314 mL | 2.8628 mL |
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