Plasma and Hepatic Concentrations of Chemicals after Virtual Oral Administrations Extrapolated Using Rat Plasma Data and Simple Physiologically Based Pharmacokinetic Models.

ABSTRACT

Only a small fraction of chemicals possesses adequate in vivo toxicokinetic data for assessing potential hazards. The aim of the present study was to model the plasma and hepatic pharmacokinetics of more than 50 disparate types of chemicals and drugs after virtual oral administrations in rats. The models were based on reported pharmacokinetics determined after oral administration to rats. An inverse relationship was observed between no-observed-effect levels after oral administration and chemical absorbance rates evaluated for cell permeability ( r = -0.98, p < 0.001, n = 17). For a varied selection of more than 30 chemicals, the plasma concentration curves and the maximum concentrations obtained using a simple one-compartment model (recently recommended as a high-throughput toxicokinetic model) and a simple physiologically based pharmacokinetic (PBPK) model (consisting of chemical receptor, metabolizing, and central compartments) were highly consistent. The hepatic and plasma concentrations and the hepatic and plasma areas under the concentration-time curves of more than 50 chemicals were roughly correlated; however, differences were evident between the PBPK-modeled values in livers and empirically obtained values in plasma. Of the compounds selected for analysis, only seven had the lowest observed effect level (LOEL) values for hepatoxicity listed in the Hazard Evaluation Support System Integrated Platform in Japan. For these seven compounds, the LOEL values and the areas under the hepatic concentration-time curves estimated using PBPK modeling were inversely correlated ( r = -0.78, p < 0.05, n = 7). This study provides important information to help simulate the high hepatic levels of potent hepatotoxic compounds. Using suitable PBPK parameters, the present models could estimate the plasma/hepatic concentrations of chemicals and drugs after oral doses using both PBPK forward and reverse dosimetry, thereby indicating the potential value of this modeling approach in predicting hepatic toxicity as a part of risk assessments of chemicals absorbed in the human body.