title: Effect of micafungin on cytochrome P450 3A4 and multidrug resistance protein 1 activities, and its comparison with azole antifungal drugs.
abstract: The effects of micafungin on cytochrome P450 3A4 (CYP3A4) metabolic and multidrug resistance protein 1 (MDR1) transport activities were investigated and compared with those of amphotericin B and four azole antifungal drugs (ketoconazole, itraconazole, fluconazole and miconazole). The effects on the metabolic activity of CYP3A4 were examined by measuring nifedipine oxidase activity in human liver microsomes and the effects on MDR1 transport activity were evaluated using [3H]digoxin in MDR1-overexpressing LLC-GA5-COL150 cells. An inhibitory effect on CYP3A4 activity was found for ketoconazole, itraconazole and miconazole, with 50% inhibitory concentrations of 11.7, 32.6 and 74.2 nM, respectively. Fluconazole and micafungin had only slight inhibitory effects and amphotericin B had no effect. The MDR1-mediated transport of [3H]digoxin was inhibited by ketoconazole and itraconazole, and slightly by miconazole. It is suggested that micafungin and amphotericin B would be unlikely to cause drug-drug interactions by inhibition of CYP3A4 and MDR1. A positive correlation between the inhibitory effects on CYP3A4 and MDR1 activities was observed, and the physicochemical mechanisms involved and impact on clinical treatment should be studied further.
authors.affiliation: Department of Hospital Pharmacy, School of Medicine, Kobe University, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. sakaedat@med.kobe-u.ac.jp
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakaeda
authors.forename: Koichi
authors.initials: K
authors.lastname: Iwaki
authors.forename: Mikio
authors.initials: M
authors.lastname: Kakumoto
authors.forename: Mika
authors.initials: M
authors.lastname: Nishikawa
authors.forename: Toshiro
authors.initials: T
authors.lastname: Niwa
authors.forename: Jiang-shu
authors.initials: JS
authors.lastname: Jin
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nakamura
authors.forename: Kohshi
authors.initials: K
authors.lastname: Nishiguchi
authors.forename: Noboru
authors.initials: N
authors.lastname: Okamura
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Okumura
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology*; D001692:Biological Transport; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D054714:Echinocandins; D006801:Humans; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D055666:Lipopeptides; D008074:Lipoproteins / Q000494:pharmacology*; D000077551:Micafungin; D008862:Microsomes, Liver / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology*; D013552:Swine
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000935:Antifungal Agents; D001393:Azoles; D065607:Cytochrome P-450 Enzyme Inhibitors; D054714:Echinocandins; D055666:Lipopeptides; D008074:Lipoproteins; D010456:Peptides, Cyclic; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000077551:Micafungin