Host: The Japanese Society of Toxicology
Name : The 47th Annual Meeting of the Japanese Society of Toxicology
Date : 2020 -
Drug metabolism and disposition of industrial chemicals with toxicity concern such as phthalates were mediated by humanized-livers in chimeric mice in the similar manner as humans in terms of biliary/urinary excretions of their glucuronides. A significant difference in the concentration-time profiles of the primary metabolite 7-hydroxywarfarin in humanized-liver mice treated with tienilic acid that cytochrome P450 2C9 was metabolically inactivated. These toxicological studies were extensively investigated by humanized-model animals. Nonetheless, in general, toxicity studies for chemicals may require significant cost and time. The main aim of the present study was to model the plasma, hepatic, and renal pharmacokinetics of disparate types of chemicals and drugs after virtual oral administrations in rats based on reported rat plasma values and experimental pharmacokinetics determined after oral administration to rats for evaluating toxicological potential. The calculated absorbance rates of the chemicals based on cell permeability studies were found to be inversely correlated to the no-observed-effect (NOEL) levels for hepatoxicity after oral administration taken from the Hazard Evaluation Support System Integrated Platform in Japan. The lowest-observed-effect level (LOEL) values in rats for oral administrations given in the database and these hepatic area under the curve values that we obtained from modeling were inversely correlated (r = -0.78, p < 0.05, n = 7). This significant example indicated the importance of simulating the hepatic levels of general chemicals, because those with high hepatic concentrations are more likely to be potent hepatotoxic compounds. These predicted effective concentrations can then be used to determine the range of test concentrations to be applied in vitro or in vivo. Where NO(A)EL/LO(A)EL and pharmaco/toxicokinetic data from in vivo studies are available, a PBPK model can be used to predict the effective concentrations in plasma and target tissues. The present simplified models could estimate the relationships between hepatic/plasma concentrations and oral doses of general chemicals using both forward and reverse dosimetry. These methods are therefore valuable for estimating hepatic toxicity.
