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PubMed1995

Physiologically based pharmacokinetic models: mathematical fundamentals and simulation implementations.

This review paper gives an overview of the building blocks of physiologically based pharmacokinetic (PBPK) models and their implementation using computer facilities. The approach focuses on the development of a PBPK model with the most important and appropriate limiting steps for the conditions and exposure scenarios under study. In this approach, the assumptions made in constructing the set of equations, as well as the fitting of variables to specific experimental results, need to be accounted for when making extrapolation to other conditions. A well-constructed PBPK model should account for all possible ranges of extrapolation from the development stages so that appropriate experimental studies and assumptions can be designed to handle the intended applications. Two common assumptions are revisited: the flow-limited assumption and the metabolic clearance using Michaelis-Menten kinetics assumption. Computer hardware and software requirements for implementing PBPK models are briefly reviewed.

Computer Simulation↗
PubMed1995

Extrapolating the future: research trends in modeling.

The proceedings in this volume suggest several important future research needs. Research is needed to validate modeling in toxicology in order to support the use of the general approach of modeling, either for structure-activity relationships (SAR) or physiologically based pharmacokinetics (PBPK), by regulators. Research is needed to demonstrate how SAR predictions can be integrated with the PBPK models to reduce the chemical-specific, intensive data requirements of PBPK models. Methods are needed to harmonize modeling approaches and to educate potential users. New approaches to modeling are needed which go beyond present day assumptions of flow-limited models into dynamic models of human health effects. The academic community can further these objectives by including applied mathematics of toxicology, including both SAR and PBPK modeling, in toxicology curricula.

Animals↗
PubMed2006

An integrated approach to model hepatic drug clearance.

It has been well accepted that hepatic drug extraction depends on the blood flow, vascular binding, transmembrane barriers, transporters, enzymes and cosubstrate and their zonal heterogeneity. Models of hepatic drug clearances have been appraised with respect to their utility in predicting drug removal by the liver. Among these models, the "well-stirred" model is the simplest since it assumes venous equilibration, with drug emerging from the outflow being in equilibrium with drug within the liver, and the concentration is the same throughout. The "parallel tube" and dispersion models, and distributed model of Goresky and co-workers have been used to account for the observed sinusoidal concentration gradient from the inlet and outlet. Departure from these models exists to include heterogeneity in flow, enzymes, and transporters. This article utilized the physiologically based pharmacokinetic (PBPK) liver model and its extension that include heterogeneity in enzymes and transporters to illustrate how in vitro uptake and metabolic data from zonal hepatocytes on transport and enzymes may be used to predict the kinetics of removal in the intact liver; binding data were also necessary. In doing so, an integrative platform was provided to examine determinants of hepatic drug clearance. We used enalapril and digoxin as examples, and described a simple liver PBPK model that included transmembrane transport and metabolism occurring behind the membrane, and a zonal model in which the PBPK model was expanded three sets of sub-compartments that are arranged sequentially to represent zones 1, 2, and 3 along the flow path. The latter model readily accommodated the heterogeneous distribution of hepatic enzymes and transporters. Transport and metabolic data, piecewise information that served as initial estimates, allowed for the unknown efflux and other intrinsic clearances to be estimated. The simple or zonal PBPK model provides predictive views on the hepatic removal of drugs and metabolites.

Animals↗
PubMed2006

Antinociceptive effects, metabolism and disposition of ketamine in ponies under target-controlled drug infusion.

Ketamine is widely used as an anesthetic in a variety of drug combinations in human and veterinary medicine. Recently, it gained new interest for use in long-term pain therapy administered in sub-anesthetic doses in humans and animals. The purpose of this study was to develop a physiologically based pharmacokinetic (PBPk) model for ketamine in ponies and to investigate the effect of low-dose ketamine infusion on the amplitude and the duration of the nociceptive withdrawal reflex (NWR). A target-controlled infusion (TCI) of ketamine with a target plasma level of 1 microg/ml S-ketamine over 120 min under isoflurane anesthesia was performed in Shetland ponies. A quantitative electromyographic assessment of the NWR was done before, during and after the TCI. Plasma levels of R-/S-ketamine and R-/S-norketamine were determined by enantioselective capillary electrophoresis. These data and two additional data sets from bolus studies were used to build a PBPk model for ketamine in ponies. The peak-to-peak amplitude and the duration of the NWR decreased significantly during TCI and returned slowly toward baseline values after the end of TCI. The PBPk model provides reliable prediction of plasma and tissue levels of R- and S-ketamine and R- and S-norketamine. Furthermore, biotransformation of ketamine takes place in the liver and in the lung via first-pass metabolism. Plasma concentrations of S-norketamine were higher compared to R-norketamine during TCI at all time points. Analysis of the data suggested identical biotransformation rates from the parent compounds to the principle metabolites (R- and S-norketamine) but different downstream metabolism to further metabolites. The PBPk model can provide predictions of R- and S-ketamine and norketamine concentrations in other clinical settings (e.g. horses).

Algorithms↗
PubMed2001

Quantitative structure-pharmacokinetic relationship modelling.

This article presents the current methods in quantitative structure-pharmacokinetic relationship (QSPkR) modelling along with examples using chemicals of toxicological significance. The common method involves: (i) collecting pharmacokinetic data or determining pharmacokinetic parameters (e.g. elimination half-life, volume of distribution) by fitting to experimental data; and (ii) associating them with the structural features of chemicals using a Free-Wilson model. Such QSPkRs have been developed for a few series of chemicals but their usefulness is limited to the exposure scenario and conditions under which the experimental data were originally collected. The alternative approach involves the development of quantitative structure-property relationship (QSPR) models for parameters, blood:air partition coefficient, tissue:blood partition coefficient, maximal velocity for metabolism and Michaelis affinity constant, of physiologically-based pharmacokinetic (PBPK) models which are useful for conducting species, route, dose and scenario extrapolations of the tissue dose of chemicals. Mechanistic QSPRs are available for predicting tissue:blood and blood:air partition coefficients from molecular structure information of chemicals, whereas such approaches are not currently available for hepatic metabolism parameters. However, at the present time, the pharmacokinetics of inhaled volatile organic chemicals can be simulated adequately by considering the physiological limits of the hepatic extraction ratio (0-1) and molecular structure-based estimates of partition coefficients in the PBPK model. This current state-of-the-art of structure-based modelling of pharmacokinetics will advance with the development of QSPRs for other chemical-specific parameters of PBPK models. Integrated QSPR-PBPK modelling should facilitate the identification of chemicals of a family that possess desired properties of bioaccumulation and blood concentration profile in both test animals and humans.

Animals↗
PubMed2002

Maintaining steady state arterial alcohol levels in rats by using a physiologically based pharmacokinetic model.

An intravenous method of alcohol administration that maintains arterial alcohol concentrations (AACs) in rats at a prescribed level for a prolonged period was previously described. This method produced steady state AACs between 30 and 180 min after the start of the infusion, but it resulted in substantial overshoots in AAC initially. The present study was designed to achieve target AACs close to steady state more quickly while minimizing any overshoot. A physiologically based pharmacokinetic (PBPK) model of alcohol distribution and elimination was developed for male Wistar rats. Body weight was used to compute individualized infusion rate profiles that would achieve steady state AACs of 75, 150, and 250 mg%. Rats were chronically implanted with cannulae in the jugular vein (for alcohol infusion) and carotid artery (for blood sampling). Alcohol was administered according to the individualized infusion rate profiles. Blood was collected at intervals for AAC determination. The PBPK model-based infusion profiles achieved target AACs 5 min after the start of the infusion and maintained the AACs for 2 h. The AACs deviated an average of 4.9%, 5.1%, and 5.9% from target at the 75, 150, and 250 mg% levels, respectively. Through the application of a PBPK model, it is possible to achieve target AACs close to steady state more quickly in male Wistar rats and to minimize any overshoot in AAC. The PBPK model-based method seems to be improved over the earlier method. Maintaining steady state AACs in rats is useful for studies in which fluctuating alcohol levels may confound experimental results.

Animals↗
PubMedDate not supplied

Characterization of a perfusion reactor utilizing mammalian cells on microcarrier beads.

Our overall objective is to develop a cell culture analogue bioreactor (CCA) that can be used together with a corresponding physiologically based pharmacokinetic model (PBPK) to evaluate molecular mechanisms of toxicity. The PBPK is a mathematical model that divides the body into compartments representing organs, integrating the kinetic, thermodynamic, and anatomical parameters of the animal. The CCA bioreactor is a physical replica of the PBPK; where the PBPK specifies organs, the CCA bioreactor contains compartments with a corresponding cell type that mimics some of the characteristic metabolism of that organ. The device is a continuous, dynamic system composed of multiple cell types that interact through a common circulating cell culture medium. The CCA bioreactor and the model can be coupled to evaluate the plausibility of the molecular mechanism that is input into the model. This paper focuses on the design, development, and characterization of a CCA bioreactor to be used in naphthalene dose response studies. A CCA bioreactor prototype developed previously is improved upon by culturing the cells on microcarrier beads. Microcarrier beads with cells attached can form packed beds with cell culture medium perfusing the beds. In this study, two packed beds of cells, one with L2 cells (rat lung) and one with H4IIE cells (rat hepatoma), are linked in a physiologically relevant arrangement by a common recirculating cell culture medium. Studies of this CCA bioreactor presented here include mixing profiles, effect of reactor environment on cell viability and intracellular glutathione, naphthalene distribution profile, and initial naphthalene dosing studies. Unlike the prototype system there is no detectable response to naphthalene addition; in a companion paper we show that this discrepancy can be explained by differences in liquid residence times in the organ compartments. The perfusion reactor design is shown to have significant operating improvements over prototype designs.

Animals↗
PubMedDate not supplied

The design and fabrication of three-chamber microscale cell culture analog devices with integrated dissolved oxygen sensors.

Whole animal testing is an essential part in evaluating the toxicological and pharmacological profiles of chemicals and pharmaceuticals, but these experiments are expensive and cumbersome. A cell culture analog (CCA) system, when used in conjunction with a physiologically based pharmacokinetic (PBPK) model, provides an in vitro supplement to animal studies and the possibility of a human surrogate for predicting human response in clinical trials. A PBPK model mathematically simulates animal metabolism by modeling the absorption, distribution, metabolism, and elimination kinetics of a chemical in interconnected tissue compartments. A CCA uses mammalian cells cultured in interconnected chambers to physically represent the corresponding PBPK. These compartments are connected by recirculating tissue culture medium that acts as a blood surrogate. The purpose of this article is to describe the design and basic operation of the microscale manifestation of such a system. Microscale CCAs offer the potential for inexpensive, relatively high throughput evaluation of chemicals while minimizing demand for reagents and cells. Using microfabrication technology, a three-chamber ("lung"-"liver"-"other") microscale cell culture analog (microCCA) device was fabricated on a 1 in. (2.54 cm) square silicon chip. With a design flow rate of 1.76 microL/min, this microCCA device achieves approximate physiological liquid-to-cell ratio and hydrodynamic shear stress while replicating the liquid residence time parameters in the PBPK model. A dissolved oxygen sensor based on collision quenching of a fluorescent ruthenium complex by oxygen molecules was integrated into the system, demonstrating the potential to integrate real-time sensors into such devices.

Animals↗
PubMed2003

A physiologically based pharmacokinetic model for oxytetracycline residues in sheep.

A physiologically based pharmacokinetic model (PBPK) for oxytetracycline (OTC) residues in sheep was developed using previously published data from a combined serum pharmacokinetic and tissue residue study [Craigmill et al. (2000) J. Vet. Pharmacol. Ther.23, 345]. Physiological parameters for organ weights and tissue blood flows were obtained from the literature. The tissue/serum partition coefficients for OTC were estimated from the serum and tissue residue data obtained at slaughter. The model was developed to include all of the tissues for which residue data were available (serum, kidney, liver, fat, muscle and injection site), and all of the remaining tissues were combined into a slowly perfused compartment with low permeability. Total body clearance of OTC calculated in the previous study was used as the starting value for clearance in the PBPK model, with the kidney being the only eliminating organ. The model was built using ACSL (Advanced Continuous Simulation Language) Graphic Modeler, and the model was fit to the serum and tissue data using the ACSL Math/Optimizer software (AEgis Technologies Group, Inc., Huntsville, AL, USA). A sensitivity analysis was also performed to determine which parameters had the greatest effect on the goodness of fit. Numerous strategies were tested to model the injection site, and a model providing a biexponential absorption of the drug from the injection bolus gave the best fit to the experimental data. The model was validated using the clearance parameters calculated from the traditional pharmacokinetic model for each individual animal in the PBPK model. This simple PBPK model well predicted OTC residues in sheep tissues after intramuscular dosing with a long-acting preparation and may find use for other species and other veterinary drugs.

Animals↗
PubMed2002

Applications of computational toxicology methods at the Agency for Toxic Substances and Disease Registry.

In its efforts to provide consultations to state and local health departments, other federal agencies, health professionals, and the public on the health effects of environmental pollutants, the Agency for Toxic Substances and Disease Registry relies on the latest advances in computational toxicology. The computational toxicology laboratory at the agency is continually engaged in developing and applying models for decision-support tools such as physiologically based pharmacokinetic (PBPK) models, benchmark dose (BMD) models, and quantitative structure-activity relationship (QSAR) models. PBPK models are suitable for connecting exposure scenarios to biological indicators such as tissue dose or end point response. The models are used by the agency to identify the significance of exposure routes in producing tissue levels of possible contaminants for people living near hazardous waste sites. Additionally, PBPK models provide a credible scientific methodology for route-to-route extrapolations of health guidance values, which are usually determined from a very specific set of experiments. Also, scientists at the computational toxicology laboratory are using PBPK models for advancing toxicology research in such areas as joint toxicity assessment and child-based toxicity assessments. With BMD modeling, all the information embedded in an experimentally determined dose-response relationship is used to estimate, with minimum extrapolations, human health guidance values for environmental substances. Scientists in the laboratory also rely on QSAR models in the many cases where consultations from the agency are reported for chemicals that lack adequate experimental documentation.

Benchmarking↗
PubMed2000

Determination of biokinetic interactions in chemical mixtures using real-time breath analysis and physiologically based pharmacokinetic modeling.

Regulatory agencies are challenged to conduct risk assessments on chemical mixtures without full information on toxicological interactions that may occur at real-world, low-dose exposure levels. The present study was undertaken to investigate the pharmacokinetic impact of low-dose coexposures to toluene and trichloroethylene in vivo in male F344 rats using a real-time breath analysis system coupled with physiologically based pharmacokinetic (PBPK) modeling. Rats were exposed to compounds alone or as a binary mixture, at low (5 to 25 mg/kg) or high (240 to 800 mg/kg) dose levels. Exhaled breath from the exposed animals was monitored for the parent compounds and a PBPK model was used to analyze the data. At low doses, exhaled breath kinetics from the binary mixture exposure compared with those obtained during single exposures, thus indicating that no metabolic interaction occurred with these low doses. In contract, at higher doses the binary PBPK model simulating independent metabolism was found to underpredict the exhaled breath concentration, suggesting an inhibition of metabolism. Therefore the binary mixture PBPK model was used to compare the measured exhaled breath levels from high- and low-dose exposures with the predicted levels under various metabolic interaction simulations (competitive, noncompetitive, or uncompetitive inhibition). Of these simulations, the optimized competitive metabolic interaction description yielded a Ki value closest to the Km of the inhibitor solvent, indicating that competitive inhibition is the most plausible type of metabolic interaction between these two solvents.

Anesthetics, Inhalation↗
PubMed2002

Development of a physiologically based pharmacokinetic model for methyl ethyl ketone in F344 rats.

A physiologically based pharmacokinetic (PBPK) model to describe the absorption, distribution, metabolism, and elimination of methyl ethyl ketone (MEK) in rats was developed. Partition coefficients were experimentally determined in rat tissues and blood samples using an in vitro vial equilibration technique. These solubility ratios were in agreement with previous human-based estimates that MEK is uniformly soluble within all tissues. The in vivo metabolism of MEK was evaluated using groups of three F344 male rats exposed to 100-2000 ppm MEK in a closed, recirculating gas uptake system. An optimal fit of a family of uptake curves was obtained by adjusting Michaelis-Menten metabolic constants, Km (affinity), and Vmax (capacity) using the PBPK model. At the highest chamber concentration, the uptake curve could not be modeled without the addition of a first-order (Kfo) metabolic pathway. Pretreatment with pyrazole, an inhibitor of oxidative microsomal metabolism, decreased the slope of the gas uptake curve but did not abolish metabolism. Optimal model fit to the gas uptake curve from pyrazole-pretreated animals required the apparent Km to be increased roughly 50 times the value determined in naive rats. The completed PBPK model was evaluated against real-time exhaled breath data collected from rats receiving an intravenous (iv) injection of MEK via a jugular vein cannula. Model simulation of the iv-treated animals required alveolar ventilation to be reduced 30% in order to match the data. Exhaled breath profiles from animals treated with MEK by oral gavage or intraperitoneal (ip) injection were evaluated and absorption rates was determined. Development of a comprehensive PBPK model for MEK in rats is the first step toward future extrapolations to apply to humans.

Administration, Oral↗
PubMedDate not supplied

Development of a physiologically based pharmacokinetic model for decane, a constituent of jet propellent-8.

Decane, a 10-carbon n-alkane and one of the highest vapor phase constituents of jet propellent-8 (JP-8), was selected to represent the semivolatile fraction for the initial development of a physiologically based pharmacokinetic (PBPK) model for JP-8. Rats were exposed to decane vapors at time-weighted average concentrations of 1200, 781, or 273 ppm in a 32-L Leach chamber for 4 h. Time-course samples for 1200 ppm and end-of-exposure samples for 781 and 273 ppm decane exposures were collected from blood, brain, liver, fat, bone marrow, lung, skin, and spleen. The pharmacokinetics of decane could not be described by flow-limited assumptions and measured in vitro tissue/air partition coefficients. A refined PBPK model for decane was then developed using flow-limited (liver and lung) and diffusion-limited (brain, bone marrow, fat, skin, and spleen) equations to describe the uptake and clearance of decane in the blood and tissues. Partition coefficient values for blood/air and tissue/blood were estimated by fitting end-of-exposure pharmacokinetic data and assumed to reflect the available decane for rapid exchange with blood. A portion of decane is speculated to be sequestered in "deep" pools in the body, unavailable for rapid exchange with blood. PBPK model predictions were adequate in describing the tissues and blood kinetics. For model validation, the refined PBPK model for decane had mixed successes at predicting tissue and blood concentrations for lower concentrations of decane vapor, suggesting that further improvements in the model may be necessary to extrapolate to lower concentrations.

Alkanes↗
PubMed2003

Physiological modeling of age-specific changes in the pharmacokinetics of organic chemicals in children.

Age-specific changes in the pharmacokinetics of chemicals are primarily due to differences in physiological and biochemical factors. For integrating the available information on the age-dependent changes in the physiological and biochemical factors, and for evaluating their combined influence on the pharmacokinetics of chemicals, physiologically based pharmacokinetic (PBPK) models are potentially useful. The objectives of this study were, therefore, (1) to assemble information on age-specific differences in physiological parameters such as alveolar ventilation rate, cardiac output, tissue volumes, tissue blood flow rates, and tissue composition for children of various age groups, and (2) to incorporate these data within a PBPK model for simulating the inhalation pharmacokinetics of a highly metabolized, volatile organic chemical (furan) in children of specific age groups (6, 10, and 14 yr old). The age-specific data on various physiological parameters were assembled following a review of the relevant literature and the hepatic metabolism rate of furan was set equal to the liver blood flow rate in adults and children. The blood:air and tissue:blood partition coefficients were calculated using molecular structure information along with the data on the blood and tissue composition (lipid and water contents) in children and adults. The PBPK model was used to simulate the pharmacokinetics of furan in adults and children (6, 10, and 14 yr old) exposed continuously for 30 h to 1 microgram/L of this chemical in inhaled air. The model simulations suggest that, for the same exposure conditions, the blood concentration of furan is likely to be greater in children by a factor of 1.5 (at steady state) than in adults, and the maximal factor of adult-children differences in liver concentration of furan metabolite is about 1.25. The PBPK model framework developed in this study should be useful for predicting the adult-children differences in internal dose of chemicals for risk assessment applications.

Adolescent↗
PubMed2004

Development of a physiologically based pharmacokinetic model for chlorobenzene in F-344 rats.

A physiologically based pharmacokinetic (PBPK) model to describe the absorption, distribution, metabolism, and elimination of chlorobenzene in rats was developed. Partition coefficients were experimentally determined in rat tissues and blood samples using an in vitro vial equilibration technique. These solubility ratios were in agreement with previous reports. The in vivo metabolism of chlorobenzene was evaluated using groups of three F344 male rats exposed to initial chlorobenzene concentrations ranging from 82 to 6750 ppm in a closed, recirculating gas uptake system. An optimal fit of the family of uptake curves was obtained by adjusting Michaelis-Menten metabolic constants, K(m) (affinity) and Vmax (capacity), using the PBPK model. At the highest chamber concentration, the uptake curve could not be modeled without the addition of a first-order (Kfo) metabolic pathway. Pretreatment with pyrazole, an inhibitor of oxidative microsomal metabolism, had no impact on the slope of the uptake curve. The completed PBPK model was evaluated against real-time exhaled breath data collected from rats receiving either an intraperitoneal (i.p.) injection or oral gavage dose of chlorobenzene in corn oil. Exhaled breath profiles were evaluated and absorption rates were determined. Development of the chlorobenzene PBPK model in rats is the first step toward future extrapolations to apply to humans.

Absorption↗
PubMedDate not supplied

Moving from external exposure concentration to internal dose: duration extrapolation based on physiologically based pharmacokinetic derived estimates of internal dose.

The potential human health risk(s) from chemical exposure must frequently be assessed under conditions for which adequate human or animal data are not available. The default method for exposure-duration adjustment, based on Haber's rule, C (external exposure concentration) or C(n) (the ten Berge modification) x t (exposure duration) = K (a constant toxic effect), has been criticized for prediction errors. A promising alternative approach to duration adjustment is based on equivalence of internal dose, that is, target-tissue dose levels, across different exposure durations. A proposed methodology for dose-duration adjustments for acute exposure guideline levels (AEGLs) based on physiologically based pharmacokinetic (PBPK) estimates of dose is illustrated with trichloroethylene (TCE). Steps in this methodology include: (1) selection and evaluation, or development and evaluation, of an appropriate PBPK model; (2) determination of an appropriate measure of internal dose; (3) estimation with the PBPK model of the tissue dose (the target tissue dose) resulting from the external exposure conditions (concentration, duration) of the critical effect; (4) estimation of the external exposure concentrations required to achieve tissue doses equivalent to the target tissue dose at exposure durations of interest; and (5) evaluation of sources of variability and uncertainty. For TCE, this PBPK modeling approach has allowed determination of dose metrics predictive of the acute neurotoxic effects of TCE and dose-duration adjustments based on estimates of internal dose.

Computer Simulation↗
PubMedDate not supplied

Partition coefficients for benzene in human skin.

The contribution of benzene to body burden after skin absorption compared with that due to inhalation absorption is of potential interest in the setting and interpretation of benzene (inhalation) exposure standards. However, an understanding of the quantitative relationship between skin and inhalation absorption, under different exposure conditions, is required. Such knowledge may be gained through physiological based pharmacokinetic (PBPK) modeling. The intake of benzene to the body via inhalation has been studied extensively. Physiological parameters enabling the calculation of amounts of benzene entering the blood stream per unit time are readily available for use in a PBPK model. Unfortunately, some data (i.e., partition coefficients) that would enable biologically plausible calculation of amounts of benzene entering the blood stream via skin absorption in a PBPK model are not available. Hence, the aim of this research was to determine partition coefficients across the epidermal and dermal layers of human skin so that these could be used within a PBPK model to determine quantitatively the flow rate of benzene per unit time through intact skin into the blood stream. The partition coefficients found for blood substitute: viable epidermis and blood substitute: dermis were, respectively, 2.4 and 11.2. Partition coefficients for benzene : stratum corneum (4.2), whole skin : blood substitute (2.2), benzene : water (109/126), and benzene : blood substitute (55/59) also were determined for the purposes of validating the blood substitute: viable epidermis and blood substitute : dermis partition coefficients.

Benzene↗
PubMed2001

A physiologically based pharmacokinetic model for methyl tert-butyl ether in humans: implementing sensitivity and variability analyses.

Methyl tert-butyl ether (MTBE) is added to gasoline to reduce carbon monoxide and ozone precursors from automobile emissions. The objectives of this study were to verify the ability of a physiologically based pharmacokinetic (PBPK) model to predict MTBE blood levels in humans and to investigate the effect of variability in the metabolism of MTBE and its influence on the predicted MTBE blood levels. The model structure for MTBE was flow-limited and had six essential compartments: lung, liver, rapidly perfused tissues, slowly perfused tissues, fat, and kidney. In this model, two pathways of metabolism are described to occur in the liver by Michaelis-Menten kinetics. Metabolic rate constants were measured in vitro using human liver microsomes and extrapolated to in vivo whole-body metabolism. Model predictions were compared with data on blood levels of MTBE taken from humans during and after a 1-h inhalation exposure to 1.7 ppm MTBE and after 4-h inhalation exposures to 4 or 40 ppm MTBE. The PBPK model accurately predicted MTBE pharmacokinetics at the high and low MTBE exposure concentrations for all time points. At the intermediate MTBE exposure concentration, however, the model underpredicted early time points while adequately predicting later time points. Results of the sensitivity analysis indicated that the influence of metabolic parameters on model output was dependent on MTBE exposure concentration. Subsequent variability analysis indicated that there was more variability in the actual measured MTBE blood levels than in the blood levels predicted by the PBPK model when using the range of metabolic parameters measured in vitro in human liver samples. By incorporating an understanding of the metabolic processes, this PBPK model can be used to predict blood levels of MTBE, which is important in determining target tissue dose estimates for risk assessment.

Administration, Inhalation↗