Cytochrome P450s (CYP) comprise a superfamily of enzymes that catalyzes the oxidation of a wide variety of xenobiotic chemicals, including drugs and carcinogens. [3][4][5] Multiple-drug therapy is a common therapeutic practice, particularly in patients with several diseases or conditions, and many drug-drug interactions involving metabolic inhibition are reported. 6,7) Antifungal drugs, including fluconazole, itraconazole, micafungin, miconazole, and voriconazole ( Fig. 1), are widely used in the treatment of systemic candidal infections and mycoses. The mechanism of action of these antifungal drugs is the inhibition of fungal CYP (14a-sterol demethylase), an enzyme responsible for the conversion of lanosterol to 14a-demethyllanosterol in the ergosterol biosynthetic pathway, 8,9) except that micafungin inhibits 1,3-b-D-glucan synthase, leading to disruption of the growing fungal cell wall and death of the fungal cell.10,11) Because antibiotics, including antifungal drugs, are coadministered in most cases, the possibility of interactions between them and other drugs exists. Recently, we have investigated the effects of antifungal drugs excluding voriconazole on CYP3A4 activity and multidrug resistance protein 1 (MDR1), and found that itraconazole and miconazole, as well as ketoconazole, had greater inhibitory effects on both CYP3A4 metabolic and MDR1 transport activities than fluconazole and micafungin.12) In addition, it has been demonstrated that the K i values of fluconazole and micafungin against nifedipine oxidation activity, a marker enzyme activity of CYP3A4, are 10.7 mM and 17.3 mM, respectively.13) Zhang et al. 14) reported that miconazole competitively inhibits several CYPs, including CYP2C9, CYP2C19, and CYP3A4, with K i values ranging from 0.01 to 7.3 mM. Furthermore, it is likely that fluconazole and voriconazole inhibit CYP2C9, CYP2C19, and CYP3A4. Post-marketing Development Research Center, Fujisawa Pharmaceutical Co., Ltd.; 3-4-7 Doshomachi, Chuo-ku, Osaka 541-8514, Japan: and b Biopharmaceutical and Pharmacokinetic Research Laboratories, Fujisawa Pharmaceutical Co., Ltd.; 2-1-6 Kashima, Yodogawa-ku, Osaka 532-8514, Japan. Received March 22, 2005; accepted May 31, 2005 The effects of five antifungal drugs, fluconazole, itraconazole, micafungin, miconazole, and voriconazole, on cytochrome P450 (CYP) 2C9-mediated tolbutamide hydroxylation, CYP2C19-mediated S-mephenytoin 4-hydroxylation, and CYP3A4-mediated nifedipine oxidation activities in human liver microsomes were compared. In addition, the effects of preincubation were estimated to investigate the mechanism-based inhibition. The IC 50 value against tolbutamide hydroxylation was the lowest for miconazole (2.0 m mM), followed by voriconazole (8.4 m mM) and fluconazole (30.3 m mM). Similarly, the IC 50 value against S-mephenytoin 4-hydroxylation was the lowest for miconazole (0.33 m mM), followed by voriconazole (8.7 m mM) and fluconazole (12.3 m mM). On the other hand, micafungin at a concentration of 10 or 25 m mM neither inhibited nor ...