Novel approach for verification of a human PBPK modeling strategy using chimeric mice in the health risk assessment of epyrifenacil.

In the human risk assessment by physiologically based pharmacokinetic modeling (PBPK), verification of the modeling strategy and confirmation of the reliability of the output data are important when the clinical data are not available. A new herbicide, epyrifenacil, is metabolized to S-3100-CA in mammals and causes hepatotoxicity in mice. S-3100-CA is transferred to the liver by transporters and eliminated by biliary excretion and metabolism. In the previous human PBPK research, we succeeded in predicting S-3100-CA pharmacokinetics by obtaining human hepatic parameters from chimeric mice with humanized liver after we checked the model's quantitative performance using mouse experimental data. To further enhance the reliability of human PBPK data, verification of the following two points was considered effective: 1) verification of model applicability to pharmacokinetics prediction in multiple animal species, and 2) verification of the parameter acquisition methods. In this study, we applied the same modeling strategy to rats, i.e., we obtained rat hepatic parameters for PBPK from chimeric mice with rat hepatocytes, not from rats. As the simulation results, rat internal dosimetry was precisely reproduced, although it tended to be slightly overestimated by approximately two times. From the results of the sensitivity analysis, this overestimation was mainly due to hepatic parameters from chimeric mice. Therefore, it is suggested that a similar slight prediction error may occur also in human PBPK using chimeric mice, but considering the degree of error, it can be said that our modeling strategy is robust and the predicted human internal dosimetry in the previous research is reliable.

Prediction of the human pharmacokinetics of epyrifenacil and its major metabolite, S-3100-CA, by a physiologically based pharmacokinetic modeling using chimeric mice with humanized liver.

Human internal dosimetry of pesticides is essential in the risk assessment when toxicity has been confirmed in laboratory animals. While human toxicokinetics data of pesticides are hardly obtained intendedly, the use of physiologically based pharmacokinetic (PBPK) modeling has become important for predicting human internal dosimetry. Especially, when the compound exhibits complicated pharmacokinetics via active uptake, metabolism, and biliary excretion in liver, it is difficult to obtain these hepatic parameters only by the in vitro experiments. Epyrifenacil, a new herbicide, is rapidly metabolized to S-3100-CA (CA) in mammals and causes hepatotoxicity in mice. CA is eliminated from the systemic circulation by biliary excretion and metabolism in liver. Although uptake of CA by transporters is observed in mouse primary hepatocytes, significantly less of it is observed in human primary hepatocytes. In order to evaluate human internal dosimetry of CA, a precise PBPK model was developed. To obtain human hepatic parameters, i.e., hepatic elimination intrinsic clearance via biliary excretion and metabolism, we used chimeric mice with humanized liver as a model to reproduce the complicated pharmacokinetics of CA in humans. After we developed a mouse PBPK model, by replacing mouse parameters with those of humans, we calculated CA concentration in human liver. Comparing the predicted CA exposure in human liver with the measured values in mice, we demonstrated a clear interspecies difference of approximately 4 times lower Cmax and AUC in humans. This result suggested that the risk of hepatotoxicity is less in humans than in mice.

Absorption, Distribution, Metabolism, and Excretion of a New Herbicide, Epyrifenacil, in Rats.

The metabolic fate of a newly developed herbicide, epyrifenacil, (ethyl[(3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl]phenoxy}pyridin-2-yl)oxy]acetate, S-3100), in rats was determined using 14C-labeled epyrifenacil. When it was administered orally to rats at 1 mg/kg, around 73-74% of the dose was absorbed, metabolized, and mainly excreted into feces within 48 h. The elimination of radioactivity in plasma and tissues was rapid, suggesting that exposure of epyrifenacil and metabolites is small. Metabolite analysis revealed that epyrifenacil was rapidly ester-cleaved to M1 and then mainly excreted into bile or further metabolized. No parent was detected in plasma, tissues, and urine. Remarkably, M1 was mainly distributed in the liver (at a concentration of 70-112 times higher than in plasma at a low dose). Furthermore, a significant sex-related difference was observed in urinary excretion of M1. Considering the above observations with those in the literature, the organic anion-transporting polypeptide (OATP) likely plays a role on the active transport of M1 in the liver and kidney.

PBPK model reporting template for chemical risk assessment applications.

Physiologically-based pharmacokinetic (PBPK) modeling analysis does not stand on its own for regulatory purposes but is a robust tool to support drug/chemical safety assessment. While the development of PBPK models have grown steadily since their emergence, only a handful of models have been accepted to support regulatory purposes due to obstacles such as the lack of a standardized template for reporting PBPK analysis. Here, we expand the existing guidances designed for pharmaceutical applications by recommending additional elements that are relevant to environmental chemicals. This harmonized reporting template can be adopted and customized by public health agencies receiving PBPK model submission, and it can also serve as general guidance for submitting PBPK-related studies for publication in journals or other modeling sharing purposes. The current effort represents one of several ongoing collaborations among the PBPK modeling and risk assessment communities to promote, when appropriate, incorporating PBPK modeling to characterize the influence of pharmacokinetics on safety decisions made by regulatory agencies.