Sterol biosynthesis inhibitors. Secondary effects and enhanced in vivo efficacy

Sterol biosynthesis inhibitors such as the imidazoles and 1,2,4-triazoles are generally regarded as inhibitors of sterol C-14 demethylation. Neither the MIC values nor the data for direct interaction with the cytochrome P-450 responsible for oxidative C-14 methyl removal, however, fully explain the observed in vivo efficacy. The first generation of azoles, which includes clotrimazole and miconazole, has been supplemented by a second generation, and azoles of the new generation are capable of additional effects on sterol biosynthesis. With the new azoles, for example, delta 5 sterols may accumulate, the accumulation being due to additional sites of inhibition in sterol biosynthesis or to direct membrane-azole interactions. Ketoconazole, itraconazole, and vibunazole are representative of the azoles of the second generation. Finally, a third generation of azoles has been discovered. Azoles of this generation, which include fluconazole, show almost negligible in vitro potency against saprophytically grown fungi but excellent in vivo efficacy. These compounds specifically affect parasitic forms of fungi, thus blocking invasion processes, and interfere directly with the plasma membrane, as shown in leakage experiments. Such secondary effects obviously enhance in vivo potency.