Favipiravir biotransformation in liver cytosol: Species and sex differences in humans, monkeys, rats, and mice

• Published in: Biopharmaceutics & drug disposition Vol. 42; no. 5; pp. 218 - 225
• Main Authors: Hanioka, Nobumitsu, Saito, Keita, Isobe, Takashi, Ohkawara, Susumu, Jinno, Hideto, Tanaka‐Kagawa, Toshiko
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01-05-2021
• Subjects: Adolescent; Adult; Aged; Aldehyde oxidase; Amides - metabolism; Animals; Antiviral Agents - metabolism; Biotransformation; Child; Child, Preschool; Cytosol; Cytosol - metabolism; favipiravir; Female; Females; Gender differences; Humans; Liver; Liver - metabolism; liver cytosol; Macaca fascicularis; Male; Males; Mice; Microsomes, Liver - metabolism; Middle Aged; Proteins; Pyrazines - metabolism; Rats; Rats, Sprague-Dawley; RNA viruses; Sex Characteristics; Sex differences; Species; Species Specificity; Young Adult; liver cytosol; favipiravir; biotransformation
• ISSN: 0142-2782; 1099-081X
• DOI: 10.1002/bdd.2275

Favipiravir is an antiviral agent effective against several RNA viruses that is converted into an inactive oxidative metabolite (M1), mainly by aldehyde oxidase, in humans. In the present study, the biotransformation of favipiravir into M1 in male and female humans, monkeys, rats, and mice was examined in an in vitro system using liver cytosolic fractions. The kinetics for M1 formation followed the Michaelis–Menten model in all species. The Km, Vmax, and CLint values in humans were 602 µM, 466 pmol/min/mg protein, and 776 nl/min/mg protein in males, respectively, and 713 µM, 404 pmol/min/mg protein, and 567 nl/min/mg protein in females, respectively. Species differences in CLint values were monkeys > humans > mice > rats in both males and females, and the variations for males and females were 120‐ and 96‐fold, respectively. Sex differences in CLint values were males > females in humans and mice, females > males in monkeys and rats, and marked variation (4.3‐fold) was noted in mice. This suggests that the roles of aldehyde oxidase in the hepatic metabolism of favipiravir differ extensively depending on the species and sex, and this study will aid in the assessment of the antiviral activities of favipiravir against novel and/or variant viruses.
Favipiravir is an anti‐viral agent effective against several RNA viruses that is converted into an inactive oxidative metabolite (M1), mainly by aldehyde oxidase, in humans. The activities in male and female humans were 297 and 241 pmol/min/mg protein, respectively. The activities in monkeys were 8.4‐fold for males and 12‐fold for females higher than those in humans, respectively. The activities in male and female rats were markedly lower than those in humans, with relative levels of 8.1% and 12%, respectively. In mice, the activity levels compared with humans were 2.0‐fold for males and 0.48‐fold for females, and a sex difference (male > female) of approximately 5‐fold was observed. This suggests that the roles of aldehyde oxidase in the hepatic metabolism of favipiravir extensively differ depending on species and sex, and this study will aid in the assessment of the anti‐viral activities of favipiravir against novel and/or variant viruses.