Metabolism of desloratadine by chimeric TK-NOG mice transplanted with human hepatocytes

Abstract

1. Desloratadine is an antiallergic drug with species-dependent metabolic profiles in mice, rats, monkeys and humans. We investigated whether humanized-liver mice could reproduce the reported human-specific in vivo metabolic profile for desloratadine in terms of the formation of 3-hydroxydesloratadine and its O-glucuronide.

2. Hepatocytes prepared from humans and humanized-liver mice both preferentially catalyzed the formation of 3-hydroxydesloratadine and its O-glucuronide in vitro.

3. After a single oral administration of desloratadine, plasma levels of desloratadine and its metabolites (3-hydroxydesloratadine and its O-glucuronide) in humanized-liver mice were lower and higher, respectively, than those in control mice.

4. The amounts of 3-hydroxydesloratadine and its O-glucuronide excreted in humanized-liver mouse feces and urine were higher than those of the control mice, whereas 5- and 6-hydroxydesloratadine formation were predominant in the feces and urine samples from control mice. A significant correlation (r = 0.68) for the dose percentage of urinary and fecal metabolites of desloratadine was only observed between the humanized-liver mice and the reported values for humans.

5. These results indicated that urinary 3-hydroxydesloratadine O-glucuronide and fecal desloratadine, 3-hydroxydesloratadine and 5-hydroxydesloratadine were the major excretion pathways of desloratadine in humanized-liver mice, which is reasonably similar to that reported for humans.

Keywords:

• Desloratadine
• humanized-liver mice
• Hu-Liver cell

Acknowledgments

The authors thank Yasuhiko Ando and Hiroaki Kato for their technical help, and Drs. Mamoru Ito, Yasuyuki Ohnishi and Hidetaka Kamimura for their helpful advice. We thank Natasha Beeton-Kempen, Ph.D., from Edanz Group (www.edanzediting.com) for editing a draft of this manuscript.

Disclosure statement

The authors report no conflict of interest.

Additional information

Funding

This work was supported by the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from AMED [Grant no. 19am0101121j0003]. Shotaro Uehara was also supported in part by the Japan Society for the Promotion of Science Grant-in-Aid for Young Scientists B [Grant no. 17K15520].