Physiologically based pharmacokinetic model for vinylidene chloride

Vinylidene chloride (VDC), a potent hepatotoxin and suspected carcinogen, is metabolized by mixed-function oxidases into a reactive metabolite(s) which is responsible for its toxicity. The metabolite is detoxified by glutathione (GSH), and liver GSH status is an important factor in the expression of VDC toxicity. A physiologically based pharmacokinetic (PB-PK) model has been developed for VDC in the rat based on oxidative metabolism of VDC and subsequent GSH detoxification of metabolite. The model offers insight into the complex interrelationship between the processes of absorption, metabolism, and GSH conjugation, and simulates the manner in which these factors operate in regulating VDC toxicity. The PB-PK model successfully predicts blood, tissue, and exhaled air concentrations of VDC, and liver GSH levels as a function of dose and route of administration. The model also explains the complex dose-response mortality curves seen with VDC. Because of the low blood:air partition coefficient of VDC and its saturable metabolism, the amount of VDC dose that is metabolized is sensitive to the rate of absorption. After an intravenous bolus dose, most of the administered VDC is exhaled unchanged within a few minutes. Blood VDC half-life is not representative of metabolism rates but to reequilibration of VDC from fat. Rats with greater fat content, therefore, display longer VDC blood half-lives. Simulations are shown to demonstrate the strength of PB-PK modeling techniques in understanding the kinetic behavior of VDC in the rat under a variety of experimental conditions.     

Physiologically based pharmacokinetic model for topotecan in mice

Topotecan is a chemotherapeutic agent of choice for the second-line treatment of recurrent ovarian cancer. In this article, we have developed a physiologically based pharmacokinetic model to characterize and predict topotecan concentrations in mouse plasma and tissues. Single intravenous (IV) doses (5, 10 and 30 mg/kg) of topotecan were administered to male Swiss Webster mice, with plasma and tissue samples collected over 24 h, and with sample analysis by high performance liquid chromatography. Topotecan disposition in the lungs, heart, muscle, skin, spleen, gut, liver, brain and adipose was described by perfusion rate-limited compartments, whereas the testes and intraperitoneal (IP) fluid were described with permeability rate-limited compartments. The kidneys were modeled as a permeability rate-limited compartment with nonlinear efflux. The model included enterohepatic recycling of topotecan, with re-absorption of drug secreted in the bile and nonlinear bioavailability. Topotecan demonstrated dose-dependent, nonlinear pharmacokinetics and its elimination was described by nonlinear clearance from the liver and a parallel nonlinear and linear clearance from the kidneys. Mean tissue-to-plasma partition coefficients ranged from 0.123 (brain) to 55.3 (kidney). The model adequately characterized topotecan pharmacokinetics in plasma and tissue for all three doses. Additionally, the model provided good prediction of topotecan pharmacokinetics from several external data sets, including prediction of topotecan tissue pharmacokinetics following administration of 1 or 20 mg/kg IV, and prediction of plasma pharmacokinetics following doses of 1, 1.25, 15, 20 and 80 mg/kg IV and 20 mg/kg IP.     

Physiologically based pharmacokinetic modeling of inhaled 2-butoxyethanol in man

The arterial blood concentration of 2-butoxyethanol (ethylene glycol monobutyl ether) was simulated in a physiologically based pharmacokinetic model developed for a 70-kg man. Elimination data (Vmax and Km) were extrapolated from the perfused rat liver, while flows and volumes were from the literature. Simulated inhalation exposure to 2-butoxyethanol at 20 ppm (0.8 mmol/m3) and physical exercise at 50 W agrees well with the results from experimental exposure of human volunteers under identical conditions. In further simulations, the marked effects of physical exercise and co-exposure to ethanol are illustrated. The relatively rapid decay of 2-butoxyethanol in all compartments indicates that the parent compound is not likely to accumulate in the body. Further, linear kinetics may be expected at occupational inhalation exposure to 2-butoxyethanol. The study serves as an example of how a physiologically based pharmacokinetic model may be used to illustrate some aspects of occupational solvent exposure.     

Physiologically based pharmacokinetic model for pralmorelin hydrochloride in rats.

Pralmorelin hydrochloride (pralmorelin), consisting of six amino acid residues, is a growth hormone-releasing peptide. The aim of this study is to analyze the pharmacokinetics of pralmorelin after intravenous bolus administration to rats, and to develop a physiologically based pharmacokinetic (PB-PK) model to describe and predict the concentrations of pralmorelin in blood and tissues. Pralmorelin (3 mg/kg) was administered intravenously to 24 Sprague-Dawley rats. Groups of three rats were sacrificed by decapitation at each designated time point (up to 4 h), and plasma and tissues (brain, lung, heart, liver, kidney, small intestine, muscle, adipose, and skin) were collected. Bile was also pooled until decapitation. The concentration of pralmorelin in samples was determined by liquid chromatography-tandem mass spectrometry. Plasma concentrations of pralmorelin declined rapidly in a biexponential manner. Biliary excretion of pralmorelin was so rapid that 80% of the dose was recovered unchanged in the bile within 1 h after administration. The distribution parameters in each tissue were obtained by using a hybrid model and an integration plot. They revealed that the distribution of pralmorelin into liver was blood flow-limited, and its distribution was permeability-limited in all other tissues. The PB-PK model developed in this study well described the time courses of pralmorelin concentration in the blood and tissues of rats.     

Physiologically based pharmacokinetic modeling of benzene metabolism in mice through extrapolation from in vitro to in vivo

Benzene (C6H6) is a highly flammable, colorless liquid. Ubiquitous exposures result from its presence in gasoline vapors, cigarette smoke, and industrial processes. Benzene increases the incidence of leukemia in humans when they are exposed to high doses for extended periods; however, leukemia risks in humans at low exposures are uncertain. The exposure-dose-response relationship of benzene in humans is expected to be nonlinear because benzene undergoes a series of metabolic transformations, detoxifying and activating, in the liver, resulting in multiple metabolites that exert toxic effects on the bone marrow. We developed a physiologically based pharmacokinetic model for the uptake and elimination of benzene in mice to relate the concentration of inhaled and orally administered benzene to the tissue doses of benzene and its key metabolites, benzene oxide, phe nol, and hydroquinone. As many parameter values as possible were taken from the literature; in particular, metabolic parameters obtained from in vitro studies with mouse liver were used since comparable parameters are also available for humans. Parameters estimated by fitting the model to published data were first-order rate constants for pathways lacking in vitro data and the concentrations of microsomal and cytosolic protein, which effectively alter overall enzyme activity. The model was constrained by using the in vitro metabolic parameters (maximum velocities, first-order rate constants, and saturation parameters), and data from multiple laboratories and experiments were used. Despite these constraints and sources of variability, the model simulations matched the data reasonably well in most cases, showing that in vitro metabolic constants can be successfully extrapolated to predict in vivo data for benzene metabolism and dosimetry. Therefore in vitro metabolic constants for humans can subsequently be extrapolated to predict the dosimetry of benzene and its metabolites in humans. This will allow us to better estimate the risks of adverse effects from low-level benzene exposures.     

Physiologically based pharmacokinetic model for developmental exposures to TCDD in the rat.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent developmental toxicant in rodents, and these effects occur at exposures similar to background human body burdens. A physiologically based pharmacokinetic (PBPK) model can aid in quantitatively describing the relationship between exposure, dose, and response. The aim of this work was the development a PBPK model to describe the relationship between maternal TCDD exposure and fetal TCDD concentrations during critical windows of susceptibility in the rat. This PBPK model is a modification of an eight-compartment model that describes the adult female rat. The modified model reduces the compartments from eight to four maternal compartments (liver, fat, placenta and rest of the body). Activation of the placental compartment and a separate fetal compartment occurs during gestation. The systemic circulation connects the maternal compartments. The physiological and biochemical parameters were obtained from the literature. The model validation used experimental data from acute and subchronic exposures prior to and during gestation. The simulations predict the TCDD tissue concentrations of the maternal compartments within the standard deviation of the experimental data. The model overestimates the fetal concentrations by approximately a factor of two at low subchronic exposures, but does predict the fetal tissue concentrations within the range of the experimental data at the higher exposures. This model may provide a framework for the development of a human PBPK model to estimate fetal TCDD concentrations in human health risk assessments.     

基于ACSL Math建立依地普仑生理药代动力学模型

目的利用ACSLMath初步建立依地普仑在人体的血流限速生理模型,并进行不同给药剂量间的外推．评估药物的体内特征。方法运用ACSL专业软件对模型进行模拟,并将预测值和文献值比较。结果预测值和文献值的相关性良好,药代动力学参数基本一致。结论模型可以较好地预测依地普仑在人体的血药时间过程．但模型仍需进一步优化和修订。     

Physiologically based pharmacokinetic model of lapatinib developed in mice and scaled to humans

Lapatinib is an oral 4-anilinoquinazoline derivative that dually inhibits epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2). This drug is a mere decade old and has only been approved by the FDA for the treatment of breast cancer since 2007. Consequently, the intricacies of the pharmacokinetics are still being elucidated. In the work presented herein, we determined the biodistribution of orally administered lapatinib in mouse plasma, brain, heart, lung, kidney, intestine, liver, muscle and adipose tissue. Using this data, we subsequently developed a physiologically based pharmacokinetic (PBPK) model of lapatinib in mice that accurately predicted the tissue concentrations after doses of 30, 60 and 90 mg/kg. By taking into account interspecies differences in physiology and physiochemistry, we then extrapolated the mouse PBPK model to humans. Our model predictions closely reflected lapatinib plasma pharmacokinetics in healthy subjects. Additionally, we were also able to simulate the pharmacokinetics of this drug in the plasma of patients with solid malignancies by incorporating a decrease in liver metabolism into the model. Finally, our PBPK model also facilitated the estimation of various human tissue exposures to lapatinib, which harmonize with the organ-specific toxicities observed in clinical trials. This first-generation PBPK model of lapatinib can be further improved with a greater understanding of lapatinib absorption, distribution, metabolism and excretion garnered from subsequent in vitro and in vivo studies and expanded to include other pharmacokinetic determinants, including efflux transporters, metabolite generation, combination dosing, etc., to better predict lapatinib disposition in both mouse and man.     

儿童生理药代动力学模型及其在儿科药物研究中的应用

生理药代动力学(physiologically based pharmacokinetic, PBPK)模型是预测药物在特殊人群中的药代动力学、药效学和安全性的重要工具。尤其对于儿童这类不易开展临床试验的人群, PBPK模型的应用更是能有效促进儿科药物的开发以及儿童的临床用药。目前, PBPK模型在儿科药物开发中的主要应用有以下几种:临床试验设计、药物相互作用(drug-drug interaction, DDI)的风险评估和儿童给药剂量的确立等。本综述简介了儿童生理药动学模型在儿科药物研究中的优越性,总结了PBPK模型如何实现从成人到儿童的外推,儿童生理药动学模型的理论基础,建模过程及所要注意的重要生理参数,列举了目前PBPK模型在儿科药物研究中的一些应用实例。最后简述了儿童PBPK模型当前的局限性和未来发展方向。     

Physiologically based pharmacokinetic/pharmacodynamic model for acrylamide and its metabolites in mice, rats, and humans

A physiologically based pharmacokinetic model was developed for acrylamide (AA) and three of its metabolites: glycidamide (GA) and the glutathione conjugates of acrylamide (AA-GS) and glycidamide (GA-GS). Liver GA-DNA adducts and hemoglobin (Hb) adducts with AA and GA were included as pharmacodynamic components of the model. Serum AA and GA concentrations combined with urinary elimination levels for all four components from male and female mice and rats were simulated from iv and oral administration of 0.1 mg/kg AA or 0.12 mg/kg GA. Adduct formation and decay rates were determined from a 6 week exposure to approximately 1 mg/kg AA in the drinking water and subsequent 6 week nonexposure period. Human urinary excretion data and Hb adduct data were utilized to extrapolate to a human model. The steady-state human liver GA-DNA adduct level from exposure to background levels of AA in the diet was predicted to be between 0.06 and 0.26 adducts per 10(8) nucleotides.     

Physiologically based pharmacokinetic model for methanol in rats, monkeys, and humans.

The pharmacokinetics of methanol and formate were characterized in male Fischer-344 rats and rhesus monkeys exposed to methanol vapor concentrations between 50 and 2000 ppm for 6 hr. End-of-exposure blood methanol concentrations were not directly proportional to the atmospheric concentration. The methanol exposures did not cause an elevation in blood formate concentrations. After an intravenous dose of [14C]methanol in rats, metabolism, exhalation, and renal excretion contributed 96.6, 2.6, and 0.8%, respectively, to the elimination of blood methanol concentrations. These values and the calculated renal methanol extraction efficiency (0.007) are nearly identical to those for humans after low doses of methanol. A physiologically based pharmacokinetic model was developed to simulate the in vivo data. In order to simulate the observed blood methanol concentrations in the inhalation studies in rats, a double pathway for methanol metabolism to formaldehyde was used. One path used rodent catalase Km and Vmax values and the other used a smaller Km and Vmax to simulate an enzyme with a higher affinity and lower capacity. The lack of proportionality observed in end-of-exposure blood methanol concentrations may be due to saturation of an enzyme with higher affinity and lower capacity than catalase. The physiologically based pharmacokinetic model was modified to simulate the monkey data and was scaled-up for humans. In order to simulate the monkey blood methanol concentrations, the use of rodent catalase parameters for methanol metabolism was required. This finding suggests that primates and rodents may be similar in the initial step of methanol metabolism after low methanol doses. Previously published human urinary methanol excretion data was successfully simulated by the model. The models were used to predict the atmospheric methanol concentration range over which the laboratory species exhibit quantitative similarities with humans. Below 1200 ppm, all three species exhibit similar end-of-exposure blood methanol concentrations and a linear relationship between atmospheric and blood methanol concentrations. At higher atmospheric concentrations, external and internal methanol concentrations increase desparately, suggesting that delivered dose rather than exposure concentration should be used in interpreting data from high-dose studies.     

Physiologically based pharmacokinetic and pharmacodynamic model for the inhibition of acetylcholinesterase by diisopropylfluorophosphate

Organophosphate (OP) exposure can be lethal at high doses while lower doses may impair performance of critical tasks. The ability to predict such effects for realistic exposure scenarios would expedite OP risk assessment. To this end, a physiologically based model for diisopropylfluorophosphate (DFP) pharmacokinetics and acetylcholinesterase (AChE) inhibition was developed in mammals. DFP tissue:blood partition coefficients, rates of DFP hydrolysis by esterases, and DFP-esterase bimolecular inhibition rate constants were determined in rat tissue homogenates. Other model parameters were scaled for rats and mice using standard allometric relationships. These DFP-specific parameter values were used with the model to simulate expected in vivo pharmacokinetic data from mice and rats. Literature data were used for model validation. DFP concentrations in mouse plasma and brain were successfully simulated after a single iv injection (B.R. Martin, 1985, Toxicol. Appl. Pharmacol. 77, 275-284). AChE inhibition and AChE resynthesis data from this study were also simulated. Effects of repeated, subcutaneous DFP dosing on AChE activity in rat plasma and brain (H. Michalek, A. Meneguz, and G.M. Bisso, 1982, Arch. Toxicol., Suppl. 5, 116-119; M.E. Traina and L.A. Serpietri, 1984, Biochem. Pharmacol. 33, 645-653) were also simulated well, but the return of brain AChE activity to basal levels after cessation of repeated dosing was not as well described. The initial model structure returned brain AChE activity to the original level, while in the laboratory studies brain AChE never returned to basal levels, even at 35 days after the last dose. These data suggest modulation of AChE synthesis with prolonged DFP exposure. This study demonstrated the possibility of using a model based on mammalian physiology and biochemistry to simulate in vivo data on DFP pharmacokinetics and AChE inhibition. Scaling of the model between rats and mice was also successful. The approach holds promise for predictive simulation of organophosphate-mediated AChE inhibition in humans.     

Physiologically based pharmacokinetic model for T84.66: A monoclonal anti-CEA antibody

Antibodies directed against tumor associated antigens are being increasingly used for detection and treatment of cancers; however, there is an incomplete understanding of the physiological determinants of antibody pharmacokinetics and tumor distribution. The purpose of this study is to (a) compare the plasma pharmacokinetics of T84.66, a monoclonal anti-CEA antibody directed against tumor associated carcinoembryonic antigen (CEA), in control and CEA expressing LS174T xenograft bearing mice, and (b) to develop a physiologically based pharmacokinetic (PBPK) model capable of integrating the influence of CEA and the IgG salvage receptor, FcRn, on T84.66 disposition. T84.66 pharmacokinetics were studied following i.v. administration (1, 10, 25 mg/kg) in control and xenograft bearing mice. In control mice, no significant differences in clearance were observed across the dose range studied. In mice bearing xenograft tumors, clearance was increased by four- to sevenfold, suggesting the presence of a “target mediated” elimination pathway. T84.66 plasma disposition was characterized with a PBPK model, and the model was applied to successfully predict antibody concentrations in tumor tissue. The PBPK model will be used to assist in the development of antibody-based targeting strategies for CEA-positive tumors. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1582–1600, 2010     

A physiologically based pharmacokinetic model for butadiene and its metabolite butadiene monoxide in rat and mouse and its significance for risk extrapolation

The gas 1,3-butadiene (BU) is an important industrial chemical and an environmental air pollutant. BU has been shown to be a weak carcinogen in the rat but a potent carcinogen in the B6C3F₁ mouse. This species difference makes risk extrapolation to humans difficult and the underlying mechanism should be clarified before meaningful risk extrapolation to humans can be made. One possible explanation for the species differences in cancer response is that there are quantitative species differences in the formation of genotoxic epoxides. To investigate this possibility a physiologically based pharmacokinetic (pbpk) model for BU together with its first reactive metabolite l,2-epoxybutene-3 (butadiene monoxide, BMO) was developed. Previously reported values on hepatic glutathione (GSH) turnover, depletion of hepatic GSH in rodents exposed to BU, and in vitro metabolic data of BU and BMO were included in the model, which incorporates intrahepatic first-pass hydrolysis of BMO and the ordered sequential, ping-pong mechanism to describe the enzyme kinetics of BMO-GSH conjugation. In vitro studies were carried out to obtain tissue: air partition coefficients of BU and BMO in rat tissue homogenates. The simulated pharmacokinetics of BU, BMO, and GSH agreed with previously published experimental observations in rat and mouse obtained in closed and open chamber experiments. According to the model, the internal dose of BMO (expressed either as the concentration in mixed venous blood or as the area under the concentration-time curve) is approximately 1.6 times higher in the mouse than in the rat for exposure to BU below 1000 ppm. At higher exposure levels, GSH depletion occurs in the mouse, but not in the rat, after about 6–9 h. This GSH depletion results in up to 2–3 times higher internal doses in the mouse than in the rat. The clear but relatively small species difference in body burdens of BMO indicated from our model can only partly explain the marked species difference in cancer response between mice and rats exposed to BU.     

Physiologically based pharmacokinetic model for beta-lactam antibiotics I: Tissue distribution and elimination in rats

The disposition characteristics of beta-lactam antibiotics in rats were investigated, and a physiologically based pharmacokinetic model capable of predicting the tissue distribution and elimination kinetics of these drugs was developed. Protein-binding parameters in rat serum were determined by equilibrium dialysis. Linear binding was found for penicillin G, methicillin, dicloxacillin, and ampicillin; however, nonlinear binding was observed for penicillin V and cefazolin. After intravenous bolus dosing, cefazolin was recovered almost completely in urine and bile, while for the penicillins, penicilloic acid was found to be the major metabolite. Biliary excretion of cefazolin followed Michaelis-Menten kinetics, and no significant inhibition of urinary secretion was observed after probenecid administration. The renal clearance of unbound drug was 0.82 ml/min with a reabsorption ratio (R) of 0.22. Tubular secretion was inhibited for the penicillins by probenecid plasma concentrations of 50 micrograms/ml, resulting in an R-value of 0.32. Erythrocyte uptake, serum protein binding, and tissue-to-plasma partition coefficient (Kp) were measured. Theoretical Kp values were calculated and found to be in good agreement with the Kp values for three of the antibiotics. Plasma and tissue concentrations (lung, heart, muscle, skin, gut, bone, liver, and kidney) were measured as a function of time at various doses for inulin and cefazolin in rats after an intravenous bolus dose, and were found to be in reasonable agreement with concentrations predicted by the model. These correlations demonstrate that the proposed model can accurately describe the plasma and tissue contributions of inulin and cefazolin in the rat and suggest that this model could have utility in predicting drug distribution in humans.     

Physiologically based pharmacokinetic modelling: a sub-compartmentalized model of tissue distribution

We present a sub-compartmentalized model of drug distribution in tissue that extends existing approaches based on the well-stirred tissue model. It is specified in terms of differential equations that explicitly account for the drug concentration in erythrocytes, plasma, interstitial and cellular space. Assuming, in addition, steady state drug distribution and by lumping the different sub-compartments, established models to predict tissue-plasma partition coefficients can be derived in an intriguingly simple way. This direct link is exploited to explicitly construct and parameterize the sub-compartmentalized model for moderate to strong bases, acids, neutrals and zwitterions. The derivation highlights the contributions of the different tissue constituents and provides a simple and transparent framework for the construction of novel tissue distribution models.     

A physiologically based pharmacokinetic model for nicotine and cotinine in man

Physiologically based pharmacokinetic (PBPK) models have been developed describing the disposition kinetics of nicotine and its major metabolite, cotinine, in man. Separate 9-compartment, flow-limited PBPK models were initially created for nicotine and cotinine. The physiological basis for compartment designation and parameter selection has been provided;chemical-specific tissue-to-blood partition coefficients and elimination rates were derived from published human and animal data. The individual models were tested through simulations of published studies of nicotine and cotinine infusions in man using similar dosing protocols to those reported. Each model adequately predicted the time course of nicotine or cotinine concentrations in the blood and urine following the administration of nicotine or cotinine. These individual models were then linked through the liver compartments to form a nicotine-cotinine model capable of predicting the metabolic production and disposition of cotinine from administered nicotine. The potential for integrating this functional PBPK model with an appropriate pharmacodynamic model for the characterization of nicotine's physiological effects is discussed.     

Physiologically based pharmacokinetic tissue compartment model selection in drug development and risk assessment

A well-stirred tank (WST) has been the predominant flow-limited tissue compartment model in physiologically based pharmacokinetic (PBPK) modeling. Recently, we developed a two-region asymptotically reduced (TAR) PBPK tissue compartment model through an asymptotic approximation to a two-region vascular-extravascular system to incorporate more biophysical detail than the WST model. To determine the relevance of a flow-limited TAR (F-TAR) approach, 75 structurally diverse drugs were evaluated herein using a priori predicted tissue:plasma partition coefficients along with hybrid and whole-body PBPK of eight rat tissues to determine the impact of model selection on simulation and optimization. Simulations showed that the F-TAR model significantly improved the ability to predict drug exposure, with hybrid and whole-body WST model error approaching 50% for tissues with larger vascular volumes. When optimization was used to fit F-TAR and WST models to pseudo data, WST-optimized drug partition coefficients more appropriately represented curve-fitting parameters rather than biophysically meaningful partition coefficients. Median F-TAR-optimized error ranged from -0.4% to +0.3%, whereas WST-optimized median error ranged from -22.2% to +1.8%. These studies demonstrated that the use of F-TAR represents a more accurate, biophysically realistic PBPK tissue model for predicting tissue exposure to drug and that it should be considered for use in drug development and regulatory review.     

Physiologically based pharmacokinetic model development and simulations for ethylene dichloride (1,2-dichloroethane) in rats

1,2-Dichloroethane (ethylene dichloride, EDC, CAS No. 107-06-2) is a chemical intermediate used in the production of vinyl chloride, trichloroethylene, vinylidene chloride, and trichloroethane. EDC is listed as a Hazardous Air Pollutant (HAP). As such, a need has been identified for a quantitative understanding of the hazards of EDC exposure by the inhalation route. Use of physiologically based pharmacokinetic (PBPK) modeling for route-to-route extrapolation of existing and a future toxicity studies conducted by the oral route may facilitate the quantitative evaluation of potential hazards posed by inhalation of EDC. PBPK models for the disposition of EDC by rats have been previously described, but a need to update the model structure and parameter values was identified based on the current understanding of kinetics of conjugation reactions mediated by glutathione-S-transferases (GSTs) and lack of fit to kinetic data that were not part of the development of previous models. Model structure updates included the addition of extrahepatic metabolism by unspecified enzymes (most likely GSTs or cytochrome P450 enzymes). Chemical-specific disposition parameters were recalibrated and provided good simulations for the majority of the large pharmacokinetic database for single or repeated exposure to EDC via inhalation, gavage, or iv injection in four strains of rats.     

Physiologically based pharmacokinetic model development and simulations for ethylene dichloride (1,2-dichloroethane) in rats

1,2-Dichloroethane (ethylene dichloride, EDC, CAS No. 107-06-2) is a chemical intermediate used in the production of vinyl chloride, trichloroethylene, vinylidene chloride, and trichloroethane. EDC is listed as a Hazardous Air Pollutant (HAP). As such, a need has been identified for a quantitative understanding of the hazards of EDC exposure by the inhalation route. Use of physiologically based pharmacokinetic (PBPK) modeling for route-to-route extrapolation of existing and a future toxicity studies conducted by the oral route may facilitate the quantitative evaluation of potential hazards posed by inhalation of EDC. PBPK models for the disposition of EDC by rats have been previously described, but a need to update the model structure and parameter values was identified based on the current understanding of kinetics of conjugation reactions mediated by glutathione-S-transferases (GSTs) and lack of fit to kinetic data that were not part of the development of previous models. Model structure updates included the addition of extrahepatic metabolism by unspecified enzymes (most likely GSTs or cytochrome P450 enzymes). Chemical-specific disposition parameters were recalibrated and provided good simulations for the majority of the large pharmacokinetic database for single or repeated exposure to EDC via inhalation, gavage, or iv injection in four strains of rats.