Itraconazole is a triazole antifungal agent. IC50 Value: N/A Target: antifungal in vitro: Itraconazole is pharmacologically distinct from other azole antifungal agents in that it is the only inhibitor in this class that has been shown to inhibit both the hedgehog signaling pathway and angiogenesis[1, 2]. These distinct activities are unrelated to inhibition of the cytochrome P450 lanosterol 14 alpha-demethylase and the exact molecular targets responsible remain unidentified. Functionally, the antiangiogenic activity of itraconazole has been shown to be linked to inhibition of glycosylation, VEGFR2 phosphorylation and cholesterol biosynthesis pathways [2].Evidence suggests the structural determinants for inhibition of hedgehog signaling by itraconazole are recognizably different from those associated with antiangiogenic activity [3]. in vivo: Nine volunteers were given either 200 mg itraconazole, or matched placebo orally once daily for 4 days. On day 4, itraconazole 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. In psychomotor tests, the interaction was statistically significant (p < 0.05) until at least 6 hours after drug administration. Inhibition of the cytochrome P450IIIA by itraconazole may explain the observed pharmacokinetic interaction [4].

• [1]. Kim, J., et al., Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth. Cancer Cell, 2010. 17(4): p. 388-99.

  [2]. Chong, C.R., et al., Inhibition of angiogenesis by the antifungal drug itraconazole. ACS Chem Biol, 2007. 2(4): p. 263-70.

  [3]. Shi, W., et al., Itraconazole side chain analogues: structure-activity relationship studies for inhibition of endothelial cell proliferation, vascular endothelial growth factor receptor 2 (VEGFR2) glycosylation, and hedgehog signaling. J Med Chem, 2011. 54(20): p. 7363-74.

  [4]. 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.