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Itraconazole
Itraconazole is a potent inhibitor of CYP3A4 which can be used as a triazole antifungal agent [1].
Cytochrome P450 3A4, abbreviated CYP3A4, is an important enzymethat oxidizessmall foreign organic molecules (xenobiotics).
In vitro: Itraconazole was metabolized into hydroxy-itraconazole (OH-ITZ), a known in vivo metabolite of ITZ, and two new metabolites: keto-itraconazole (keto-ITZ) and N-desalkyl-itraconazole (ND-ITZ). Itraconazole was a substrate for CYP3A and to characterize the metabolites generated. Itraconazole exhibited an unbound Km of 3.9 nM for CYP3A. Itraconazole metabolites are as potent as or more potent CYP3A4 inhibitors than ITZ itself [1]. Itraconazole was pharmacologically distinct from other azole antifungal agents. Itraconazole has been shown to inhibit both the hedgehog signaling pathway and angiogenesis [2] Itraconazole was active against 60 clinical isolates of Aspergillus spp. with geometric mean (GM) MICs of 0.25 mg/mL [3]. Itraconazoleshowed an affinity for mammalian cytochrome P-450 enzymes as well as for fungal P-450-dependent enzyme, and thus has the potential for clinically important interactions [4].
In vivo: Oral Administration of itraconazole (200 mg) once daily for 4 days increased the area under the midazolam concentration-time curve from 10 to 15 times (p < 0.001) and mean peak concentrations three to four times (p < 0.001) compared with the placebo phase [5].
References:
[1].?Isoherranen N1,Kunze KL,Allen KE,Nelson WL,Thummel KE. Role of itraconazole metabolites in CYP3A4 inhibition.Drug Metab Dispos.2004 Oct;32(10):1121-31. Epub 2004 Jul 8.
[2].?Kim J1,Tang JY,Gong R,Kim J,Lee JJ,Clemons KV,Chong CR, et al. Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth.Cancer Cell.2010 Apr 13;17(4):388-99. doi: 10.1016/j.ccr.2010.02.027.
[3].?Oakley KL1,Moore CB,Denning DW. In vitro activity of SCH-56592 and comparison with activities of amphotericin B and itraconazole against Aspergillus spp.Antimicrob Agents Chemother.1997 May;41(5):1124-6.
[4].?Leyden J1. Pharmacokinetics and pharmacology of terbinafine and itraconazole.J Am Acad Dermatol.1998 May;38(5 Pt 3):S42-7.
[5].?Olkkola, K.T., J.T. Backman, and P.J. Neuvonen, Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole. Clinical Pharmacology & Therapeutics, 1994. 55(5): p. 481-485.
| Physical Appearance | A solid |
| Storage | Store at -20°C |
| M.Wt | 705.63 |
| Cas No. | 84625-61-6 |
| Formula | C35H38Cl2N8O4 |
| Solubility | insoluble in EtOH; insoluble in H2O; ≥8.83 mg/mL in DMSO |
| Chemical Name | 2-butan-2-yl-4-[4-[4-[4-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one |
| SDF | Download SDF |
| Canonical SMILES | CCC(C)N1C(=O)N(C=N1)C2=CC=C(C=C2)N3CCN(CC3)C4=CC=C(C=C4)OCC5COC(O5)(CN6C=NC=N6)C7=C(C=C(C=C7)Cl)Cl |
| Shipping Condition | Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice. |
| General tips | We do not recommend long-term storage for the solution, please use it up soon. |
| Cell experiment [1]: | |
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Cell lines |
C. glabrata, C. kefyr |
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Preparation method |
The solubility of this compound in DMSO is > 8.8mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reacting condition |
0.016 μg/ml |
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Applications |
Itraconazole showed antifungal activity against 206 isolates of C. glabrata. For 144 isolates, two or more replicate test results were recovered from the database. In five replicate tests with two bioassay strains of C. kefyr (SA and ATCC 46764), the IC50 of itraconazole was 0.016 mg/L. |
| Animal experiment [2]: | |
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Animal models |
CD1 mice model of disseminated candidiasis |
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Dosage form |
5 mg/kg, twice daily for 5 days |
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Application |
Treatment with ITZ led to lower numbers of CFU per gram of kidney. The survival rates for mice inoculated with strain Sr and isolate B were 7 of 10 in mice treated with ITZ. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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References: [1]. Odds F C, Bossche H V. Antifungal activity of itraconazole compared with hydroxy-itraconazole in vitro[J]. Journal of Antimicrobial Chemotherapy, 2000, 45(3): 371-373. [2]. Valentin A, Le Guennec R, Rodriguez E, et al. Comparative resistance of Candida albicans clinical isolates to fluconazole and itraconazole in vitro and in vivo in a murine model[J]. Antimicrobial agents and chemotherapy, 1996, 40(6): 1342-1345. | |
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