IngentaConnect Effect of micafungin on cytochrome P450 3A4 and multidrug resista...

Authors: Sakaeda, Toshiyuki¹; Iwaki, Koichi¹; Kakumoto, Mikio¹; Nishikawa, Mika¹; Niwa, Toshiro²; Jin, Jiang-shu¹; Nakamura, Tsutomu¹; Nishiguchi, Kohshi¹; Okamura, Noboru³; Okumura, Katsuhiko¹

Source: Journal of Pharmacy and Pharmacology, Volume 57, Number 6, June 2005 , pp. 759-764(6)

Publisher: Pharmaceutical Press

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.

Document Type: Research article

DOI: 10.1211/0022357056118

Affiliations: 1: Department of Hospital Pharmacy, School of Medicine, Kobe University, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan 2: Post-marketing Development Research Center, Fujisawa Pharmaceutical Co., Ltd, 3-4-7, Doshomachi, Chuo-ku, Osaka, 541-8514, Japan 3: Department of Clinical Evaluation of Pharmacotherapy, Kobe University Graduate School of Medicine, 1-5-6, Minatojimaminamimachi, Chuo-ku, Kobe 650-0047, Japan

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Effect of micafungin on cytochrome P450 3A4 and multidrug resistance protein 1 activities, and its comparison with azole antifungal drugs