Differences in Pharmacokinetics and Haematotoxicities of Aniline and Its Dimethyl Derivatives Orally Administered in Rats

Abstract

Aniline and its dimethyl derivatives reportedly become haematotoxic after metabolic N-hydroxylation of their amino groups. The plasma concentrations of aniline and its dimethyl derivatives after single oral doses of 25 mg/kg in rats were quantitatively measured and semi-quantitatively estimated using liquid chromatography-tandem mass spectrometry. The quantitatively determined elimination rates of aniline; 2,4-dimethylaniline; and 3,5-dimethylaniline based on rat plasma versus time curves were generally rapid compared with those of 2,3-; 2,5-; 2,6-; and N,2-dimethylaniline. The primary acetylated metabolites of aniline; 2,4-dimethylaniline; and 3,5-dimethylaniline, as semi-quantitatively estimated based on their peak areas in liquid chromatography analyses, were more extensively formed than those of 2,3-; 2,5-; 2,6-; and N,2-dimethylaniline. The areas under the curve of unmetabolized (remaining) aniline and its dimethyl derivatives estimated using simplified physiologically based pharmacokinetic models (that were set up using the experimental plasma concentrations) showed an apparently positive correlation with the reported lowest-observed-effect levels for haematotoxicity of these chemicals. In the case of 2,4-dimethylaniline, a methyl group at another C 4 -positon would be one of the determinant factors for rapid metabolic elimination to form aminotoluic acid. These results suggest that rapid and extensive metabolic activation of aniline and its dimethyl derivatives occurred in rats and that the presence of a methyl group at the C 2 -positon may generally suppress fast metabolic rates of dimethyl aniline derivatives that promote metabolic activation reactions at NH 2 moieties.

Updated <i>in Silico</i> Prediction Methods for Fractions Absorbed and Key Input Parameters of 355 Disparate Chemicals for Physiologically Based Pharmacokinetic Models for Time-Dependent Plasma Concentrations after Virtual Oral Doses in Humans

“…We could successfully generate PBPK model input parameters for rat models calculated from a small number of chemical properties by machine-learning prediction tools. 26) Rat PBPK modeling 31) will also make increasingly important contributions to computational toxicology and facilitate assessment of the potential risks of industrial or food chemicals. In terms of human PBPK modeling, the previously used ridge regression approach 32) is a method for estimating the coefficients of multiple-regression models.…”

“…8,9) Simplified PBPK models that use some fixed physiological system parameters are easier to handle than full PBPK models and are of use in the fields of drug discovery, poisoning, or therapeutic drug monitoring 7,[10][11][12] as well as in risk assessment for a variety of general chemicals or food components/additives. 13) Although the metabolic profiles of disparate chemicals (including aromatic amines 14,15) ) traditionally have been elucidated in rodent studies, 16) so-called new alternative methods (NAMs) for evaluating chemical safety have been widely investigated using in silico or in vitro approaches. 17,18) The approach that applies simple PBPK modeling, without any reference to experimental pharmacokinetic data, has the potential to play significant roles in replacing and reducing the use of animals for estimating toxicokinetics or internal exposures of drugs, food components, and general chemicals.…”

Forward and reverse dosimetry for aniline and 2,6-dimethylaniline in humans extrapolated from humanized-liver mouse data using simplified physiologically based pharmacokinetic models

“…Nonetheless, the tolerable daily intake (TDI) value of aniline has been set by the United States Environmental Protection Agency at 7.0 µg/kg/day (Chinthakindi and Kannan, 2022b). Aniline and 2,6-dimethylaniline are both metabolized to hematotoxic N-hydroxylated metabolites and excretable glucuronide conjugates of their amino groups (Miura et al, 2021a;Lewalter and Korallus, 1985;Gonçalves et al, 2001). Aromatic amines, including aniline and 2,6-dimethylaniline, have been detected in indoor Correspondence: Hiroshi Yamazaki (E-mail: hyamazak@ac.shoyaku.ac.jp) air, cigarette smoke, and indoor dust collected in several countries (Chinthakindi and Kannan, 2021;Stabbert et al, 2003;Zhang et al, 2017;Palmiotto et al, 2001;Kannan, 2022b, 2022a).…”

“…Physiologically based pharmacokinetic (PBPK) modeling is a generally recognized method for estimating toxicokinetics (Wambaugh et al, 2015(Wambaugh et al, , 2018Sayre et al, 2020). Simplified PBPK models constructed using chemical receptor, metabolizing, excreting, and central compartments have been developed for a range of substances and species (Miura et al, 2021a(Miura et al, , 2020b(Miura et al, , 2021b. The elimination rate of 2,6-dimethylaniline from rat plasma was slower than that of aniline, and we previously demonstrated that differences in the pharmacokinetics of aniline and its dimethyl derivatives in rats estimated by PBPK modeling were related to the existence of a methyl group at the C 2 -position (Miura et al, 2021a).…”

“…Simplified PBPK models constructed using chemical receptor, metabolizing, excreting, and central compartments have been developed for a range of substances and species (Miura et al, 2021a(Miura et al, , 2020b(Miura et al, , 2021b. The elimination rate of 2,6-dimethylaniline from rat plasma was slower than that of aniline, and we previously demonstrated that differences in the pharmacokinetics of aniline and its dimethyl derivatives in rats estimated by PBPK modeling were related to the existence of a methyl group at the C 2 -position (Miura et al, 2021a). However, it is not known whether the slow elimination of dimethyl derivatives compared with that of aniline itself would also be seen in humans.…”