Studies on stereoselective separations of the “azole” antifungal drugs ketoconazole and itraconazole using HPLC and SFC on silica-based polysaccharides

The incidence of serious fungal infections has increased dramatically in recent decades. This increase is mainly due to the advent of HIV and to the increased use of cancer chemotherapy and of immunosuppressive therapies in organ transplantation [1,2]. The treatment of fungal diseases involves several classes of antifungal agents, among which the imidazoleor triazole-based drugs (referred to collectively as the “azoles”) constitute a large and important group [3]. The azoles are, at present, the only antifungal agents with good oral bioavailability and activity against a broad spectrum of fungal pathogens. However, the azoles are not free from adverse side effects. For example, some azoles, e.g. ketoconazole (KETO) and itraconazole (ITRA), are potent inhibitors of cytochrome P450 (CYP) 3A4, an important drug-metabolizing enzyme, and such inhibition of CYP can cause severe and sometimes even fatal drug-drug interactions [4,5]. Thus, there is clearly a need for safer azole antifungal agents.