A system for predicting apparent bidirectional permeability (Papp) across Caco-2 cells of diverse chemicals has been reported. The present study aimed to investigate the relationship between in silico-generated Papp (from apical to basal side, Papp A to B) for 301 substances with diverse structures and a binary classification of the reported roles of efflux P-glycoprotein or breast cancer resistant protein. The in silico log(Papp A to B/Papp B to A) values of 70 substances with reported active efflux and 231 substances with no reported active efflux were significantly different (p < 0.01). The probabilities of active efflux transport estimated by trivariate analysis with log MW, log DpH 6.0, and log DpH 7.4 for the 70 active-efflux-positive compounds were higher than those of the other 231 substances (p < 0.01); the area under the corresponding receiver operating characteristic (ROC) curve was 0.81. Further probability values estimated using a machine learning algorithm with 30 chemical descriptors as inputs yielded an area under the ROC curve of 0.79. Using a secondary set of 52 efflux-positive and 48 efflux-negative medicines, the final trivariate-generated probabilities resulted in no significant differences between these binary groups (p = 0.09); however, the final machine learning model demonstrated a good area under the ROC curve of 0.79. Consequently, a combination of the previously established system for generating the permeability coefficients across intestinal monolayers (a continuous variable) and the currently proposed system for predicting the roles of additional active efflux (a binary classification) could prove useful; high accuracy was achieved by applying machine learning using in silico-generated chemical descriptors.
Tetrabromobisphenol A, a brominated flame retardant, is increasingly prevalent worldwide and presents a potential health risk. Adjusted animal biomonitoring equivalents of tetrabromobisphenol A after orally administered doses in humanized-liver mice were scaled up to humans using known species allometric scaling factors to set up simplified physiologically based pharmacokinetic (PBPK) models. Absorbed tetrabromobisphenol A was slightly, moderately, and extensively metabolized in vivo to its glucuronide in rats, control mice, and humanized-liver mice tested, respectively. In silico estimated hepatic exposures of tetrabromobisphenol A and its glucuronide generated using the rat PBPK model-generated plasma concentration profiles were consistent with the reported values. The extent of hepatic injury in humanized-liver mice caused by tetrabromobisphenol A was evaluated by detecting human albumin mRNA in mouse plasma after oral administration of a high dose of tetrabromobisphenol A (1000 mg/kg). Reverse dosimetry analyses were carried out using two human PBPK models (set up based on the humanized-liver-mouse model and by optimizing the input parameters for reported human plasma concentrations of tetrabromobisphenol A glucuronide) to estimate the tetrabromobisphenol A daily intake based on reported human serum concentrations of total tetrabromobisphenol A from biomonitoring data. Within the predictability of the forward and reverse dosimetry estimations, the calculated daily intake was found to be far below established health benchmark levels (i.e., the suggested daily reported reference dose) with a wide (4 orders of magnitude) safety margin. These results suggest that the simplified PBPK models can be successfully applied to forward and reverse dosimetry estimations of tissue and/or blood exposures of tetrabromobisphenol A in humans after oral doses.
Coumarin is a dietary-derived substance that is extensively metabolized by human liver to excretable 7-hydroxycoumarin. Although coumarin under daily dietary consumption is generally regarded as nontoxic, the substance is of toxicological and clinical interest because of its potential association with hepatotoxicity, which is especially evident in rats. In this study, the pharmacokinetics of coumarin were modeled after virtual oral administration in humans. The adjusted monitoring equivalents of coumarin, along with the biotransformation of coumarin to o-hydroxyphenylacetic acid (via 3,4-epoxidation) based on reported plasma concentrations from rat studies, were scaled to human coumarin equivalents using known species allometric scaling factors. Using rat and human liver preparations, data on the rapid in vitro metabolic clearance for humans (~50-fold faster than in rats) were obtained for in vitro-in vivo extrapolation. For human physiologically based pharmacokinetic (PBPK) modeling, the metabolic ratios to o-hydroxyphenylacetic acid and 7-hydroxycoumarin were set at minor (0.1) and major (0.9) levels for the total disappearance of coumarin. The resulting modeled plasma concentration curves in humans generated by simple PBPK models were consistent with reported simulated coumarin maximum concentrations. These results provide basic information to simulate plasma levels of coumarin and its primary metabolite 7-hydroxycoumarin or its secondary activated metabolite o-hydroxyphenylacetic acid (via 3,4-epoxidation) resulting from dietary foodstuff consumption. Under the current assumptions, little toxicological impact of coumarin was evident in humans, thereby indicating the usefulness of forward dosimetry using PBPK modeling for human risk assessment.
Abstract We previously analysed the serum concentrations of dihydrocodeine in a 1‐month‐old infant with respiratory depression after being prescribed dihydrocodeine phosphate 2.0 mg/day divided t.i.d. for 2 days. The purpose was to develop a full physiologically based pharmacokinetic (PBPK) model that could account for these and other drug monitoring results. Based on experiments in Caco‐2 cell monolayers, the effective permeability of dihydrocodeine in human jejunum was established as 1.28 × 10 −4 cm/s. The in vitro V max /K m values for dihydrocodeine demethylation mediated by recombinant cytochrome P450 2D6 and 3A4 were 0.19 and 0.066 μl/min/pmol, respectively, and for dihydrocodeine 6‐ O ‐glucuronidation mediated by recombinant UGT2B4 and 2B7, the V max /K m values were 0.14 and 0.22 μl/min/mg protein, respectively. Renal clearance was calculated as 5.37 L/h on the total clearance value multiplied by the fraction recovered in urine. The reported plasma concentration–time profiles of dihydrocodeine after intravenous administration in healthy volunteers were used to adjust the tissue partitioning ratios. The developed model simulated the pharmacokinetic profiles of dihydrocodeine after single and multiple oral administrations reasonably well in the same population. Subsequently, the validated model was used to simulate pharmacokinetic profiles for five pediatric cases, including the 1‐month‐old Japanese boy and a 14‐year‐old Japanese girl who took an overdose of dihydrocodeine phosphate (37 mg). The simulated pharmacokinetic profiles for five virtual pediatric subjects matching the age, gender, and P450 2D6 phenotype of each case approximately reflected the observed values. These results suggested that our dihydrocodeine PBPK model reproduced the results of clinical cases reasonably well for subjects.
A simplified physiologically based pharmacokinetic (PBPK) model consisting of chemical receptor, metabolizing and/or excreting, and central compartments was recently proposed. In the current study, this type of PBPK model was set up for perfluorooctane sulfonate, an environmental toxicant with liver effects, as a model compound; the model was then used to estimate tissue concentrations. The pharmacokinetic parameter input values for the model were calculated to give the best fit to reported/measured blood substrate concentrations in rats. The maximum concentrations and areas under the concentration versus time curves in plasma, liver, and kidney extrapolated using PBPK models for perfluorobutane sulfonic acid, perfluorohexane sulfonic acid, and perfluorooctane sulfonic acid were consistent with the reported mean values in rats. Using the rat models and scaled-up human PBPK models, some accumulation of perfluorooctane sulfonic acid in plasma and liver was seen after repeated doses. The reported 50th and 95th percentile concentrations of perfluorooctane sulfonic acid in human blood (0.0048 and 0.0183 ng/mL, respectively) in the general population underwent reverse dosimetry analysis using our PBPK models. These human blood concentrations potentially imply exposures of 0.041 and 0.16 µg/kg/day, respectively, for 90 days, values that are roughly similar to the reference dose (0.02 μg/kg/day) with an uncertainty factor of 30. These results indicate the relatively good estimates for tissue and blood exposures of chemical substrates after oral doses generated using the latest PBPK models.
We reported that the introduction of polyethylene glycol (PEG) to poly-l-ornithine (PLO), which is an homopolymeric basic amino acid having absorption-enhancement ability, prolonged retention time in an in vitro inclined plate test, probably due to an increase in viscosity caused by PEGylation. The aim of the present study is to investigate whether the introduction of PEG chains to PLO improves intranasal retention and transnasal absorption in vivo. We performed intranasal administration experiments using PLO and PEG-PLO with a model drug, fluorescein isothiocyanate dextran (FD-4), in rats under closed and open systems. In the open system, transition of plasma FD-4 concentration after co-administration with unmodified PLO was low, and the area under the plasma concentration-time curve (AUC) decreased to about 60% of that in the closed system. In contrast, the AUC after co-administration with PEG-PLO in the open system was about 90% of that in the closed system, and the transition of plasma FD-4 concentration and FD-4 absorption profile were similar to those of the closed system. These findings indicate that introducing PEG chains to homopolymeric basic amino acids (HPBAAs) is a very useful method for developing a functional absorption enhancer that can exhibit an efficient in vivo absorption-enhancing effect.
Aniline and its dimethyl derivatives reportedly become haematotoxic after metabolic N-hydroxylation of their amino groups. The plasma concentrations of aniline and its dimethyl derivatives after single oral doses of 25 mg/kg in rats were quantitatively measured and semi-quantitatively estimated using LC-tandem mass spectrometry. The quantitatively determined elimination rates of aniline; 2,4-dimethylaniline; and 3,5-dimethylaniline based on rat plasma versus time curves were generally rapid compared with those of 2,3-; 2,5-; 2,6-; and N,2-dimethylaniline. The primary acetylated metabolites of aniline; 2,4-dimethylaniline; and 3,5-dimethylaniline, as semi-quantitatively estimated based on their peak areas in LC analyses, were more extensively formed than those of 2,3-; 2,5-; 2,6-; and N,2-dimethylaniline. The areas under the curve of unmetabolized (remaining) aniline and its dimethyl derivatives estimated using simplified physiologically based pharmacokinetic models (that were set up using the experimental plasma concentrations) showed an apparently positive correlation with the reported lowest-observed-effect levels for haematotoxicity of these chemicals. In the case of 2,4-dimethylaniline, a methyl group at another C
Lenalidomide has been shown to be potentially teratogenic in thalidomide-sensitive animal species. Screening for thalidomide analogs devoid of teratogenicity/toxicity—attributable to drug metabolism and disposition, but having immunomodulatory properties—is a strategic pathway towards development of new anticancer drugs. Plasma concentrations of lenalidomide were investigated in immunodeficient control and humanized-liver mice following oral administration of lenalidomide (50 mg/kg). Plasma concentrations of lenalidomide (1-2 hr after administration) were slightly but significantly higher in humanized-liver mice than in control mice (p < 0.05). Human albumin mRNA, a liver-specific toxicity marker, was found in the blood of humanized-liver mice 24 hr after lenalidomide administration. Simulations of human plasma concentrations of lenalidomide were achieved with simplified physiologically-based pharmacokinetic models in control and humanized-liver mice or by the direct fitting analysis of reported human data, in accordance with reported lenalidomide concentrations after low dose administration in humans. The results indicate that pharmacokinetic profiles of lenalidomide, a compound resulting from introducing one aromatic amino group into thalidomide and removing one keto group, resulted in less species variation in in vivo pharmacokinetics in control and humanized-liver mice and that immunodeficient humanized-liver mice can serve as experimental model animals for human liver injury in drug development at high doses, with human albumin RNA analysis in plasma.
