Different Hepatic Concentrations of Bromobenzene, 1,2-Dibromobenzene, and 1,4-Dibromobenzene in Humanized-Liver Mice Predicted Using Simplified Physiologically Based Pharmacokinetic Models as Putative Markers of Toxicological Potential

Abstract

Bromobenzene is an industrial solvent that elicits toxicity predominantly in the liver. In this study, the hepatic concentrations of bromobenzene and its related compounds 1,2dibromobenzene and 1,4-dibromobenzene in humanized-liver mice were predicted after single oral administrations by simplified physiologically based pharmacokinetic (PBPK) models that had been set up on experimental plasma concentrations after single oral doses of 100 mg/kg to rats and 100−250 mg/kg to control mice and humanized-liver mice. The output values by simplified PBPK models were consistent with measured blood substrate concentrations in rats, control mice, and humanized-liver mice with suitable input parameter values derived from in silico prediction and the literature or estimated by fitting the measured plasma substrate concentrations. The predicted time-dependent hepatic concentrations after virtual administrations in humanized-liver mice were partly confirmed with single measured hepatic concentrations of bromobenzene and 1,4-dibromobenzene 2 h after oral doses of 150−250 mg/kg to humanized-liver mice. Moreover, leaked human albumin mRNA, a marker of the extent of human hepatic injuries, in humanized-liver mouse plasma was detected after oral administration of bromobenzene, 1,2-dibromobenzene, and 1,4dibromobenzene. These results suggest that dosimetry approaches for determining tissue and/or blood exposures of hepatic toxicants bromobenzene, 1,2-dibromobenzene, and 1,4-dibromobenzene in humanized-liver mice were useful after virtual oral doses using simplified PBPK models. Using simplified PBPK models and plasma data from humanized-liver mice has potential to predict and evaluate the hepatic toxicity of bromobenzenes and related compounds in humanized-liver mice and in humans.

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

“…Simplified rat PBPK models consisting of gut, liver, kidney, and central compartments were set up for aniline and its dimethyl derivatives 10,17) . The values of the plasma unbound fraction (f u,p ), octanol-water partition coefficient (logP), blood-to-plasma concentration ratio (R b ), and the liver-to-plasma or kidney-to-plasma concentration ratio (K p,h or K p,r ) for aniline and its dimethyl derivatives were calculated using in silico tools (Simcyp and ChemDraw software) as described previously 18,19) ; the results are shown in Table 1.…”

“…The values of the plasma unbound fraction (f u,p ), octanol-water partition coefficient (logP), blood-to-plasma concentration ratio (R b ), and the liver-to-plasma or kidney-to-plasma concentration ratio (K p,h or K p,r ) for aniline and its dimethyl derivatives were calculated using in silico tools (Simcyp and ChemDraw software) as described previously 18,19) ; the results are shown in Table 1. The values used for the hepatic and renal blood flow rates (Q h and Q r ) in rats were 0.853 L/h, and hepatic and renal volumes of 8.5 mL (8.5 g) and 3.7 mL (3.7 g), respectively, were used as described previously 10,17) . Initial values for the fraction absorbed × intestinal availability (F a •F g ), the hepatic clearance (CL h ), and the renal clearance (CL r ) for PBPK modelling were derived from the elimination constants obtained using one-compartment models.…”

“…The lowest-observed-effect levels (LOELs) of many haematotoxic compounds are available from the Hazard Evaluation Support System Integrated Platform (HESS) 9) . We recently reported that the differences in the pharmacokinetics of bromobenzene; 1,2-dibromobenzene; and 1,4-dibromobenzene administered to rats and to humanized-liver mice were related to the positions of the bromo substituents 10) . There are only a limited number of reports on the urinary excretion of aniline 3) , but the relationship between the positions of the aniline substituents and their oxidative metabolism has not been extensively researched in experimental animals or in humans.…”

Pharmacokinetics of primary oxidative metabolites of thalidomide in rats and in chimeric mice humanized with different human hepatocytes

“…Three male Sprague-Dawley rats (7 weeks old, Charles River Laboratory, Tokyo, Japan) and 20 male humanized-liver immunodeficient TK-NOG mice (20-30 g body weight) (Hasegawa et al, 2011) were used in this study. Four differ-ent sources of human hepatocytes were used: lot BPI-HEP187273, genotyped as CYP3A5*3/*3, was obtained from Biopredic, St Gregoire, France, whereas lots TRL-HUM4122B, genotyped as CYP3A5*1/*3; TRL-HUM4119F, genotyped as CYP3A5*1/*7; and TRL-HUM4129, genotyped as CYP3A5*3/*3 were obtained from Lonza TRL, Morrisville, NC, USA (Miura et al, 2019b(Miura et al, , 2020(Miura et al, , 2021. After liver-specific damage was induced in the TK-NOG mice, these human hepatocytes were transplanted to reconstitute the liver.…”

Metabolic profiles for the pyrrolizidine alkaloid neopetasitenine and its metabolite petasitenine in humans extrapolated from rat <i>in vivo</i> and <i>in vitro</i> data sets using a simplified physiologically based pharmacokinetic model

“…Sprague-Dawley rats (three males, 7 weeks old, Charles River Laboratory, Tokyo, Japan) and rat liver microsomes and 9000 × g supernatant liver fractions (S9) prepared previously (Miura et al, 2020a(Miura et al, , 2020b were used. This study was approved by the Institutional Animal Care and Use Committees of Shin Nippon Biomedical Laboratories and Showa Pharmaceutical University.…”