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Biomedical subjects

M E Andersen

Publications and source records attributed to M E Andersen.

At least 37 records · Page 2Linked to original sources
PubMed1999

Dosimetric adjustment factors for methyl methacrylate derived from a steady-state analysis of a physiologically based clearance-extraction model.

Cells within the epithelial lining of the nasal cavity metabolize a variety of low-molecular-weight, volatile xenobiotics. In common with terminology developed for other metabolizing organs, the nose extracts these chemicals from the airstream, thereby clearing some portion of the total nasal airflow. In this article, a physiologically based clearance-extraction (PBCE) model of nasal metabolism is used to predict extraction for steady-state conditions. This model, developed by simplification of existing physiologically based pharmacokinetic (PBPK) nasal models, has three tissue regions in two flow paths. A dorsal flow stream sequentially passes over a small area of respiratory epithelium and then over the entire olfactory epithelial surface within the nose. A ventral airstream, consisting of most of the total flow, passes over the larger portion (>80%) of the respiratory epithelium. Each underlying tissue stack has a mucus layer, an epithelial tissue compartment, and a blood exchange region. Metabolism may occur in any of the subcompartments within the tissue stacks. The model, solved directly for a steady-state condition, specifies the volumetric airflow over each stack. Computational fluid dynamic (CFD) solutions for the rat and human for the case with no liquid-phase resistance provided a maximum value for regional extraction, E(max)'. Equivalent air-to-liquid phase permeation coefficients (also referred to as the air-phase mass transfer coefficient) were calculated based on these E(max)' values. The PBCE model was applied to assess expected species differences in nasal extraction and in localized tissue metabolism of methyl methacrylate (MMA) in rats and in humans. Model estimates of tissue dose of MMA metabolites (in micromol metabolized/h/ml tissue) in both species were used to evaluate the dosimetric adjustment factor (DAF) that should be applied in reference concentration (RfC) calculations for MMA. For human ventilation rates equivalent to light exercise, the DAF was estimated to be 3.02 at 28.4 ppm, the benchmark concentration for nasal lesions. Depending on specific assumptions about distribution of esterase activities in human tissues, the range of DAF values was 1.56-8.00. The DAF for heavy exercise with a ventilation rate of 42 L/min was still 2.98. Estimated DAFs were concentration dependent, varying between 2.4 and 4.76 in the inhaled concentration range from 1 and 400 ppm. Present default methods utilize a DAF of 0.145. These steady-state calculations with this PBCE model should be useful in risk assessment calculations for a variety of vapors and gases that are converted to toxic metabolites in cells in the respiratory tract.

Acetates↗
PubMed1999

Biological regulation of receptor-hormone complex concentrations in relation to dose-response assessments for endocrine-active compounds.

Some endocrine-active compounds (EACs) act as agonists or antagonists of specific hormones and may interfere with cellular control processes that regulate gene transcription. Many mechanisms controlling gene expression are universal to organisms ranging from unicellular bacteria to more complex plants and animals. One mechanism, coordinated control of batteries of gene products, is critical in adaptation of bacteria to new environments and for development and tissue differentiation in multi-cellular organisms. To coordinately activate sets of genes, all living organisms have devised molecular modules to permit transitions, or switching, between different functional states over a small range of hormone concentration, and other modules to stabilize the new state through homeostatic interactions. Both switching and homeostasis are regulated by controlling concentrations of hormone-receptor complexes. Molecular control processes for switching and homeostasis are inherently nonlinear and often utilize autoregulatory feedback loops. Among the biological processes contributing to switching phenomena are receptor autoinduction, induction of enzymes for ligand synthesis, mRNA stabilization/activation, and receptor polymerization. This paper discusses a variety of molecular switches found in animal species, devises simple quantitative models illustrating roles of specific molecular interactions in creating switching modules, and outlines the impact of these switching processes and other feedback loops for risk assessments with EACs. Quantitative simulation modeling of these switching mechanisms made it apparent that highly nonlinear dose-response curves for hormones and EACs readily arise from interactions of several linear processes acting in concert on a common control point. These nonlinear mechanisms involve amplification of response, rather than multimeric molecular interactions as in conventional Hill relationships.

Animals↗
PubMed1999

A biologically based risk assessment for vinyl acetate-induced cancer and noncancer inhalation toxicity.

The 1990 Clean Air Act Amendments require that health risk from exposure to vinyl acetate be assessed. Vinyl acetate is a nasal carcinogen in rats, but not mice, and induces olfactory degeneration in both species. A biologically based approach to extrapolating risks of inhalation exposure from rats to humans was developed, which incorporates critical determinants of interspecies dosimetry. A physiologically based pharmacokinetic (PBPK) model describing uptake and metabolism of vinyl acetate in rat nose was validated against nasal deposition data collected at three airflow rates. The model was also validated against observations of metabolically derived acetaldehyde. Modifying the rat nose model to reflect human anatomy created a PBPK model of the human nose. Metabolic constants from both rats and humans specific for vinyl acetate and acetaldehyde metabolism enabled predictions of various olfactory tissue dosimeters related to the mode of action. Model predictions of these dosimeters in rats corresponded well with observations of vinyl acetate toxicity. Intracellular pH (pHi) of olfactory epithelial cells was predicted to drop significantly at airborne exposure concentrations above the NOAEL of 50 ppm. Benchmark dose methods were used to estimate the ED10 and LED10 for olfactory degeneration, the precursor lesion thought to drive cellular proliferation and eventually tumor development at excess cellular acetaldehyde levels. A concentration x time adjustment was applied to the benchmark dose values. Human-equivalent concentrations were calculated by using the human PBPK model to predict concentrations that yield similar cellular levels of acetic acid, acetaldehyde, and pHi. After the application of appropriate uncertainty factors, an ambient air value of 0.4 to 1.0 ppm was derived. The biologically based approach supports a workplace standard of 10 ppm.

Acetaldehyde↗
PubMed1999

Quantitative mechanistically based dose-response modeling with endocrine-active compounds.

A wide range of toxicity test methods is used or is being developed for assessing the impact of endocrine-active compounds (EACs) on human health. Interpretation of these data and their quantitative use in human and ecologic risk assessment will be enhanced by the availability of mechanistically based dose-response (MBDR) models to assist low-dose, interspecies, and (italic)in vitro(/italic) to (italic)in vivo(/italic) extrapolations. A quantitative dose-response modeling work group examined the state of the art for developing MBDR models for EACs and the near-term needs to develop, validate, and apply these models for risk assessments. Major aspects of this report relate to current status of these models, the objectives/goals in MBDR model development for EACs, low-dose extrapolation issues, regulatory inertia impeding acceptance of these approaches, and resource/data needs to accelerate model development and model acceptance by the research and the regulatory community.

Dose-Response Relationship, Drug↗
PubMed1998

Dose-response characteristics of uterine responses in rats exposed to estrogen agonists.

Assays for uterine response have played major roles in developing an understanding of estrogen-mediated processes and for identifying compounds with hormonal activity. Data from assays measuring increases in uterine wet weight in rats were evaluated in terms of their dose-response characteristics. Analysis using a Hill equation found inconsistent estimates for the ED50 (concentration giving half-maximal response) and n (steepness of response) among the assays. This variability reflects disparate assay protocols and limitations of the dose-response data collected in the experiments. Although uterine wet weight is easily measured, it arises from several physiological processes (e.g., water retention, cell proliferation). This contributes to the assay variability with different protocols. The potential use of the Hill equation for dose-response analysis to estimate a benchmark dose was also considered using these data sets as surrogates for receptor-mediated toxicological effects. Strengths and weaknesses were identified, but overall the Hill equation should likely become a favored option for determining a benchmark dose, particularly when a data set demonstrates a maximal response. For screening purposes, empirical analysis using the Hill equation provides adequate information for classifying and prioritizing compounds. To develop an understanding of how incremental exposures to compounds with estrogen agonist activities would affect intact adult females, quantitative analyses are required that account for the pharmacokinetics of estradiol and subsequent interactions of the receptor complexes in regulating the responses.

Animals↗
PubMed1998

A physiologically based pharmacokinetic description of the oral uptake, tissue dosimetry, and rates of metabolism of bromodichloromethane in the male rat.

Bromodichloromethane (BDCM), a trihalomethane (THM) and water chlorination by-product, induces cancer in several tissues in experimental animals, including target tissue sites where increased incidences of human cancer have been linked to consumption of chlorinated water. The purpose of the present study was to examine the effects of vehicle of administration on the pharmacokinetics of orally administered BDCM and to further develop and validate a physiologically based pharmacokinetic (PBPK) model to describe BDCM absorption, tissue dosimetry, and rates of metabolism for both oil and 10% Emulphor vehicles. Estimates of oral absorption rate constants were determined by fitting blood and exhaled breath chamber concentration-time curves obtained following gavage of male F344 rats with 50 or 100 mg BDCM/kg in corn oil or 10% Emulphor using a previously published multicompartmental gastrointestinal tract submodel (Semino et al., Toxicology 117, 25-33, 1997) linked to a PBPK model. Independently estimated oral uptake and metabolic rate constants accurately described kidney BDCM concentrations and plasma bromide ion levels without adjustment. This observation increases our confidence in model structure and values of parameter estimates. Liver BDCM concentrations were simulated, but with less accuracy than kidney dosimetry simulations, following incorporation of BDCM loss to metabolism during sample preparation. This model describes BDCM tissue dosimetry and metabolism following oral gavage and can be utilized in estimating rates of formation of reactive metabolites in target tissues. Estimates of tissue dosimetry and levels of toxic intermediates can be incorporated into a risk assessment model for BDCM-induced toxicity and carcinogenicity.

Administration, Oral↗
PubMed1998

A model for pharmacokinetics and physiological feedback among hormones of the testicular-pituitary axis in adult male rats: a framework for evaluating effects of endocrine active compounds.

The testicular-hypothalamic-pituitary axis controls reproductive functions in males. A description of the basic physiological interactions in adult rats among testosterone, luteinizing hormone (LH), and follicle stimulating hormone (FSH) was developed, permitting simulation of hormone levels in testes and blood. This model was used to simulate hormone levels in intact, castrate, ethane dimethanesulfonate-treated, and antiandrogen-treated rats. A large gradient of testosterone concentrations from testicular interstitial fluid to low levels in peripheral blood is created by the testicular blood flow. The dominant feedback loop is positive regulation of testosterone synthesis by LH and negative feedback of testosterone on LH and FSH. The utility of the model for placing in vitro data in the context of in vivo physiology was illustrated for the case of continued synthesis of testosterone by the isolated testes. In the absence of blood flow, very low residual testosterone synthesis can substantially increase testosterone concentration in isolated testes. Effects of an exogenous endocrine active compound were illustrated by modeling altered LH and FSH regulation by testosterone in the presence of an antiandrogen acting as a competitive ligand for the androgen receptor. Increasing concentrations have no effect on steady-state hormone levels until sufficient levels of antiandrogen are achieved to reduce negative feedback of testosterone on LH and FSH. In summary, a model has been developed that provides a basis for initiating evaluations of key issues of concern for the risk assessment of endocrine active compounds including in vitro to in vivo extrapolation and their dose-response behaviors.

Animals↗
PubMed1998

Kinetic characterization of CYP2E1 inhibition in vivo and in vitro by the chloroethylenes.

Trans- and cis-1,2-dichloroethylene (DCE) isomers inhibit their own metabolism in vivo by inactivation of the metabolizing enzyme, presumably the cytochrome P450 isoform, CYP2E1. In this study, we examined cytochrome P450 isoform-specific inhibition by three chloroethylenes, cis-DCE, trans-DCE, and trichloroethylene (TCE), and evaluated several kinetic mechanisms of enzyme inhibition with physiological models of inhibition. Trans-DCE was more potent than cis-DCE, and both were much more effective than TCE in inhibiting CYP2E1. The kinetics of in vitro loss of p-nitrophenol hydroxylase (pNP-OH) activity (a marker of CYP2E1) in microsomal incubations and of the in vivo gas uptake results were most consistent with a mechanism in which inhibition of the metabolizing enzyme (CYP2E1) was presumed to be related to interaction of a reactive DCE metabolite with remaining substrate-bound, active CYP2E1. The kinetics of inhibition by TCE, a weak inhibitor in vitro, were very different from that of the dichloroethylenes. With TCE, parent compound concentrations influenced enzyme loss. Trans-DCE was a more potent inhibitor of CYP2E1 than cis-DCE based on both in vivo and in vitro studies. Quantitative differences in the inhibitory properties of the 1,2-DCE isomers may be due to the different stability of epoxides formed from bioactivation by CYP2E1. Epoxide intermediates of DCE metabolism, reacting by water addition, would yield dialdehyde, a potent cross-linking reagent.

Animals↗
PubMed1998

Endocrine active compounds: from biology to dose response assessment.

Endocrine active compounds (EACs) alter signaling processes responsible for regulation and coordination of physiological functions during development and adulthood. The potential that adverse effects of these compounds have gone unrecognized has focused attention on their toxicology. The primary response to this concern has been development of additional hazard identification methods. This review discusses issues for dose response (DR) analyses for EACs, including definitions of adversity, implications of alternative modes of action, the roles homeostatic and developmental regulatory feedback processes play in creating DR behaviors, uses of in vitro data in DR analyses, and induction of effects by natural and synthetic compounds in the context of endogenous hormone background. Current risk assessment guidance applicable to endocrine-mediated effects provide limited default methods for evaluating DR behaviors and making interspecies comparisons. Improved DR methods for EACs will be achieved through the use of mode of action and dosimetry data to better characterize potential human risks.

Animals↗
PubMed1998

The use of biochemical and molecular parameters to estimate dose-response relationships at low levels of exposure.

Biomarkers based on alterations in molecular and biochemical parameters may be useful in chemical risk assessment for establishing the presence of an exposure, ranking relative risks among exposed individuals, and estimating risks at low levels of exposure. Because it is unlikely that the relation between toxic responses and the degree of alteration in the biomarker is equivalent at all doses, quantification of risks at low levels is not necessarily more accurate using these biomarkers for extrapolation. The application of response biomarkers for risk evaluation at low levels of exposure is discussed in relation to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a compound that causes induction of cytochromes CYP1A1 and CYP1A2 in liver and other tissues. CYP1A1 induction in liver increases monotonically with TCDD dosage; however, several of the dose-response curves for hepatic effects of TCDD are U-shaped. The U-shaped dose-response curve for hepatic tumor promotion appears to result because the integrated toxicologic response depends on multiple underlying processes--mitosuppression, toxicity, and cell proliferation--each of which has a different dose-response relationship with respect to TCDD. Although dose-response relationships for the biomarkers are not expected to duplicate the complex shapes seen with the integrated responses, measurements and pharmacodynamic modeling of the changes in these molecular and biochemical parameters can still be useful for obtaining an upperbound risk estimate at low levels of exposure.

Animals↗
PubMed1997

Physiologically based estimation of in vivo rates of bromodichloromethane metabolism.

Bromodichloromethane (BDCM) is a rodent carcinogen formed by chlorination of drinking water containing bromide and organic precursors. BDCM is a member of the class of disinfection by-products known as trihalomethanes (THMs), compounds that have been shown to be carcinogenic in rodents. A physiologically-based pharmacokinetic (PBPK) model has been developed and applied to provide estimates of the rates of metabolism of BDCM in vivo in rats. The model consists of five compartments (liver, kidney, fat and slowly and rapidly perfused tissues). Tissue partition coefficients were determined using a modified vial equilibration technique and rates of metabolism were estimated by fitting data obtained from stable metabolite (bromide ion, (Br-)) analysis following 4 h constant concentration BDCM inhalation exposure (50-3200 ppm) and closed chamber gas uptake experiments. Metabolism was described using a single saturable pathway representing a high capacity, high affinity process (Vmaxc = 12.8 mg/h/kg; Km = 0.5 mg/l). Rate constants obtained from Br- data adequately described data from gas uptake experiments and literature data on exhalation of 14CO and 14CO2 produced following oral gavage with 14C-BDCM. Pretreatment with trans-dichloroethylene (t-DCE), an inhibitor of CYP2E1, increased the apparent Km from 0.5 to 225 mg/l indicating that CYP2E1 is the major P450 isoform involved in the bioactivation of BDCM to reactive intermediates.

Animals↗
PubMed1997

Pharmacodynamic model of the rat estrus cycle in relation to endocrine disruptors.

Several strains of laboratory rats have a high background incidence of mammary tumors and develop a persistent, anovulatory estrus condition at about 12 mo of age. The increased tumor incidence is believed to be associated with elevated estradiol (E2) and prolactin during the period of persistent estrus. A pharmacodynamic estrus cycle (PD-EC) model for the Sprague-Dawley rats has been developed in an attempt to analyze the physiological basis of early-onset persistent estrus and to examine the potential sites of interactions in the hypothalamic-pituitary-ovarian axis for endocrine-modulating xenobiotics that accelerate the onset of persistent estrus. This initial estrus cycle model focused solely on cyclical changes in E2 and luteinizing hormone (LH). An LH surge was scheduled when a hypothetical estrus cycle-related protein (EC-RP) under transcriptional control by the E2 receptor reached a critical concentration. In the model, aging-related cumulative hypothalamic E2 exposure impaired the LH surge by reducing the rate of production of the EC-RP. The progressively decreasing intercycle resynthesis rate leads first to longer, variable-length cycles and finally to persistent estrus at about 12 mo of age. This model construct is consistent with early-onset persistent estrus related to neonatal E2 exposures, with acyclicity associated with high-dose E2 exposure in the adult, and with persistent estrus conditions associated with exposures to xenobiotic endocrine modulators that are either weak E2 antagonists or weak E2 agonists. With further development these pharmacodynamic estrus cycle models should be useful in aiding risk assessments for compounds causing mammary-tissue tumors associated with persistent estrus states.

Aging↗
PubMed1997

A pharmacokinetic model describing pulsatile uptake of orally-administered carbon tetrachloride.

Many rodent bioassays have been conducted using oral gavage for delivery of test chemicals. Highly lipophilic compounds are generally administered to rodents dissolved in corn oil, a dosing vehicle shown to influence xenobiotic toxicity, carcinogenicity and pharmacokinetics by altering chemical absorption processes. In this paper, we present a multi-compartmental description of the gastrointestinal (GI) tract linked to a physiologically based pharmacokinetic (PB-PK) model to describe the complex oral uptake of carbon tetrachloride (CCl4) administered in corn oil and 0.25% Emulphor. The GI submodel was described using a series of subcompartments, each subcompartment described with an absorption constant (Ka, 1/h), a bioavailability term (A, unitless), and a compartment emptying time (T, h). The model was parameterized by fitting multi-peak blood and exhaled breath chamber concentration-time profiles following oral gavage of CCl4 in corn oil and aqueous vehicles to male Fischer 344 rats. Successful fitting of experimental data was accomplished by varying values of Ka, A, and T until adequate fits were obtained. Values of Ka and A required to fit data from aqueous gavage were greater than corn oil. Utilization of the multi-compartmental GI tract submodel provided increased precision in fitting complex oral uptake profiles compared to previously used one- and two-compartment oral uptake models. This model provides estimates of absorption rate constants and bioavailabilities as well as providing a framework for generation of more complete, physiologically-realistic descriptions of oral absorption.

Administration, Oral↗
PubMed1997

Implementation of EPA Revised Cancer Assessment Guidelines: Incorporation of Mechanistic and Pharmacokinetic Data.

A workshop entitled "Implementation of EPA Revised Cancer Assessment Guidelines: Incorporation of Mechanistic and Pharmacokinetic Data" was held in Anaheim, California, in 1996 at the 35th Annual Meeting of the Society of Toxicology (SOT). This workshop was jointly sponsored by the Carcinogenesis, Risk Assessment, and Veterinary Specialty Sections of the SOT. The thrust of the workshop was to discuss the scientific basis for the revisions to the EPA Guidelines for cancer assessment and EPA's plans for their implementation. This is the first revision to the original EPA guidelines which have been in use by EPA since 1986. The principal revisions are intended to provide a framework for an increased ability to incorporate biological data into the risk assessment process. Two cases were presented, for chloroform and triclioroethylene, that demonstrated the use of the revised guidelines for specific cancer risk assessments. Using these new guidelines, nonlinear margin of exposure analyses were proposed for these chemicals instead of the linearized multistage model previously used by the EPA as the default method. The workshop participants generally applauded the planned revisions to the EPA guidelines. For the most part, they considered that the revised guidelines represented a positive step which should allow for and encourage the use of biological information in the conduct of cancer risk assessments. Several participants cautioned however that the major problem with cancer risk assessments would continue to be the inadequacy of available data on which to conduct more scientific risk assessments.

Animals↗
PubMed1997

Dose-response assessment strategies for endocrine-active compounds.

Hazard identification provides evidence for the potential of compounds to cause effects in exposed people. Dose-response assessments define the range of exposure conditions associated with minimal risks of adverse effects. With endocrine-active compounds (EACs), the vast majority of resources are presently being applied to hazard identification. In the past, dose-response assessments have been based on empirical analysis of these relationships. The empirical underpinnings of these models do not permit conclusions about the low-dose and interspecies extrapolation of the animal study results. Biologically based dose-response assessments relying on knowledge of mode-of-action (pharmacodynamics) and dosimetry (pharmacokinetics) offer promise to develop broadly applicable strategies for quantitative dose-response assessments with these EACs. These approaches would focus on normal physiological endocrine signaling processes in the body, their associated control mechanisms, and the interaction among different internal signaling pathways. A critical element of signaling is regulation of the concentration of the signaling compound, e.g., steroid sex hormone. Exogenous compounds that act as signals but evade the normal homeostatic control of signaling compound concentrations represent one class of EACs. Other molecular components of these signaling systems include receptors, second messengers, and DNA-accessory/transcriptional protein complexes; EACs may interfere with the functions of any of these components. The challenge facing the toxicology and risk assessment professions is to base regulatory strategies on the interaction of these EACs with the fundamental control mechanisms which regulate responses throughout the body and to determine the extent to which these interactions create specific dose-response behaviors in the living animals.

Carrier Proteins↗
PubMed1997

Physiologically based modeling of vinyl acetate uptake, metabolism, and intracellular pH changes in the rat nasal cavity.

Chronic inhalation exposure to vinyl acetate (VA) causes lesions in the nasal cavity of the rat. This effect appears to be related to tissue exposure to either acetaldehyde (AAld) or acetic acid (AA) metabolites of VA or both. A physiologically based pharmacokinetic model was constructed to describe the deposition of VA in the nasal cavity of the rat and provide estimates of regional tissue exposure to VA, AAld, and AA. Since formation of AA in the nasal tissue should cause intracellular acidification, a submodel which describes free intracellular hydrogen ion concentration and intracellular pH (pHi) changes was linked to the VA model. The dosimetry model was applied to data from a series of experiments designed to measure the uptake and metabolism of VA in the isolated upper respiratory tract of the rat at exposure concentrations ranging from 73 to 2190 ppm. Extraction of VA from the nasal cavity was nonlinear with respect to exposure concentration and ranged from 36 to 94%, with the greatest deposition occurring at the lowest VA concentrations. Pretreatment with bis(p-nitrophenyl)phosphate, an inhibitor of carboxylesterases, significantly reduced fractional deposition of VA compared to naive rats exposed to similar VA concentrations. The best model fits for VA extraction and AAld appearance were achieved when a second carboxylesterase isozyme, with high-affinity characteristics, was included. Simulations of 6-h inhalation exposures to VA predicted that the order of nasal tissue exposures will be to AA > AAld > VA. In addition, based on measured tissue hydrolysis rates, sufficient acid should be formed by the metabolism of VA to cause significant changes in pHi. VA exposures of 200 and 600 ppm were predicted to result in a pHi of less than 7.2 and 6.7, respectively. This model provides nasal dosimetry estimates needed to develop mechanistically based risk assessment approaches for human exposures to VA vapor.

Acetaldehyde↗
PubMed1997

A multicompartment geometric model of the liver in relation to regional induction of cytochrome P450s.

A geometric, multicompartment model of the liver was developed to examine regional protein induction and to provide model output suitable for predicting the degree of induction in both the whole liver and in specific regions. The model was based on functional hexagonal arrays within the liver. A geometric representation was used to divide these functional units into five zones: a concentric periportal zone, a fenestrated periportal region that interconnects among multiple functional units, and three concentric centrilobular areas, referred to, respectively, as zones 1 through 5. The surface areas (and volumes for hexagonal cylinders) of these live zones were, respectively, 13.5, 25.2, 33.9, 20.3, and 6.8% of the total liver. The pharmacokinetic model for induction had dissociation constants (Kd) and Hill constants (n) for interactions of transcriptional activator-ligand complexes with response elements on DNA. Estimates of regional induction were converted to color intensities to "paint" the two-dimensional liver for a visual comparison with immunohistochemical observations. To obtain sharp moving boundaries of induced areas with increasing dose (as noted in various experiments), n values in each subcompartment must be large. To create realistic total induction curves that are relatively smooth, the differences in Kd values between adjacent subcompartments must be less than fivefold. Because of the high n values, the low-dose induction characteristics predicted with the multicompartment liver model differ significantly from those predicted with a model that considers the liver as a single homogeneous compartment.

Animals↗