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.

Adult and infant pharmacokinetic profiling of dihydrocodeine using physiologically based pharmacokinetic modeling

“…To estimate the permeability of dihydrocodeine in human jejunum, its apparent permeability in a Caco‐2 monolayer system was determined following the reported method (Kamiya et al, ). The in vitro kinetic parameters for dihydrocodeine were experimentally determined using recombinant human P450 2D6/3A4 (Uehara et al, ) and UGT2B4/2B7 (Uno et al, ), according to our reported methods.…”

Human plasma and liver concentrations of styrene estimated by combining a simple physiologically based pharmacokinetic model with rodent data

“…Simplified PBPK models for styrene (molecular weight: 104.15) consisted of a chemical receptor (gut) compartment, a metabolizing (liver) compartment, and a central compartment with a peripheral compartment and were established as previously described (Kamiya et al, 2019;Yamazaki et al, 2016). The octanol-water partition coefficient (logP: 2.86) and the plasma unbound fraction (f u,p : 0.136) of styrene were estimated in silico using ChemBioDraw and Simcyp (Emoto et al, 2009).…”

“…The concentrations of styrene in plasma were also taken from the literature (Withey, 1976). The volume of the systemic circulation (V 1 ), the absorption rate constant (k a ), and the in vivo hepatic intrinsic clearance (CL h,int ) were evaluated using nonlinear regression analysis fitting techniques, as described previously (Kamiya et al, 2019). The renal clearance (CL r ) was set at a minimum value compared with the hepatic clearance (CL h ).…”

“…The parameters required for the simplified human PBPK model for styrene were determined from the parameters of the rat PBPK model, from physiological parameters derived from the literature, and from the results of the liver microsomal experiments. The values of k a , V 1 , and CL h , for styrene in humans were estimated using a scale-up strategy from rats to humans, as described previously (Takano et al, 2010;Yamazaki et al, 2016;Kamiya et al, 2019). Briefly, the human k a value was obtained by multiplying the rat absorption rate constant (k a ) by 0.744; the human systemic circulation volume (V 1,human ) was estimated using V h and the blood volume (V b ), with V h,human , V b,rat , and V b,human values of 1.50, 0.0160, and 4.90 L, respectively (Yamashita et al, 2014): where V d is the volume of distribution per unit body weight and F h is the unmetabolized fraction in liver.…”

Pharmacokinetics of anticoagulant edoxaban in overdose in a Japanese patient transported to hospital

“…However, such PBPK models are impractical for widespread daily use in clinical hospital pharmacies to support the care of a verity of patients. Against this background, we proposed simple PBPK models for drugs for practical use by paramedical staff [8]. A prototype PBPK simulator [9] for creating the visualized plasma concentration curves for important medicines by easy input was provided by our group and has been currently updated and modified.…”