• Takahiro Yamada, Yasuaki Mino, Takafumi Naito, and Junichi Kawakami.
• Department of Hospital Pharmacy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan.
• J. Infect. Chemother. 2019 Dec 1; 25 (12): 1019-1025.

AbstractFlavin-containing monooxygenase (FMO) 3 together with cytochrome P450 (CYP) 2C19 play a significant role in voriconazole N-oxidation. This study aimed to evaluate the influence of FMO3 and CYP2C19 genotypes on the plasma disposition and adverse effects of voriconazole in immunocompromised patients. Sixty-five Japanese immunocompromised patients receiving oral voriconazole were enrolled. Predose plasma concentrations of voriconazole and N-oxide were determined at day 5 or later. The adverse effects of voriconazole and the FMO3 and CYP2C19 genotypes were investigated. The patients with FMO3 E158K/E308G had a lower plasma concentration of voriconazole. The metabolic ratio to N-oxide was significantly higher in the FMO3 E158K/E308G group than in the wild group. In contrast, FMO3 V257M was not associated with the plasma concentration of voriconazole. No significant difference was observed in the saturation index, defined as a correlation coefficient of the regression line between the absolute plasma concentration of voriconazole and the inverse value of the metabolic ratio to N-oxide, between the FMO3 genotypes. CYP2C19 phenotype did not affect the plasma concentration and metabolic ratio of voriconazole. The saturation index of voriconazole rose in the order of CYP2C19 extensive, intermediate, and then poor metabolizer groups. However, the FMO3 and CYP2C19 genotypes and their associated voriconazole pharmacokinetics did not have an effect on the incidence of adverse effects. In conclusion, FMO3 E158K/E308G decreased the plasma concentration of voriconazole through its higher metabolic activity. The FMO3 genotype altered the plasma exposure of voriconazole, while the CYP2C19 phenotype affected the metabolic capacity in immunocompromised patients.Copyright © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

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