Hepatotoxicological potential of P-toluic acid in humanised-liver mice investigated using simplified physiologically based pharmacokinetic models.
Xenobiotica
; 51(6): 636-642, 2021 Jun.
Article
em En
| MEDLINE
| ID: mdl-33781181
ABSTRACT
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.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.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.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.
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Base de dados:
MEDLINE
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Fígado
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Modelos Biológicos
Limite:
Animals
Idioma:
En
Revista:
Xenobiotica
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Japão