Hepatotoxicological potential of P-toluic acid in humanised-liver mice investigated using simplified physiologically based pharmacokinetic models

Abstract

1. p-Toluic acid, a metabolite of organic solvent xylene, has a high reported no‐observed‐effect level (NOEL, 1000 mg/kg) in rats, possibly because of direct glycine conjugation to methylhippuric acid. In this study, plasma levels of p-toluic acid and its glycine conjugate in mice and humanised-liver mice were evaluated after oral administrations.

2. Although rapid conversion of p-toluic acid to its glycine conjugate was evident from mouse plasma concentrations, the biotransformation of p-toluic acid was slower in humanised-liver mice. The input parameters for physiologically based pharmacokinetic (PBPK) models were determined using fitting procedures to create PBPK-generated plasma concentration curves.

3. The PBPK-modelled hepatic concentrations of p-toluic acid in humanised-liver mice were higher than those observed in plasma. PBPK-modelled hepatic and plasma concentrations of p-toluic acid also indicated slow elimination in humans.

4. These results suggest that rapid conjugations of p-toluic acid reportedly observed in rats could result in overestimation of NOELs for conjugatable chemicals when extrapolated to humanised-liver mice or humans.

Keywords:

• Chimeric mice
• circulating human albumin mRNA
• hepatic exposure
• humanised liver
• PBPK modelling

Acknowledgments

We are grateful to Fumiaki Shono, Masato Kitajima, Akiko Toda, Masayuki Mogi, Yui Kobayashi, Mayu Yanagi, Kazuki Shigeta, Shiori Hina, Airi Kato, Wataru Kobari, Jun Tomizawa, Masaya Fujii, and Shohei Otsuka for their support and assistance. We also thank David Smallbones for copyediting a draft of this article.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported in part by the Ministry of Economy, Trade and Industry’s Artificial Intelligence-based Substance Hazard Integrated Prediction System Project, Japan. TM and YK were partly supported by the Japan Society for the Promotion of Science Grants-in-Aid for Young Scientists [202021210] and Early-Carrier Scientists [19K16422], respectively.