Background:

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].

参考文献:
[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.