Six-compartment Model Research Articles

A six-compartment model for COVID-19 with transmission dynamics and public health strategies.

The global crisis of the COVID-19 pandemic has highlighted the need for mathematical models to inform public health strategies. The present study introduces a novel six-compartment epidemiological model that uniquely incorporates a higher isolation rate for unreported symptomatic cases of COVID-19 compared to reported cases, aiming to enhance prediction accuracy and address the challenge of initial underreporting. Additionally, we employ optimal control theory to assess the cost-effectiveness of interventions and adapt these strategies to specific epidemiological scenarios, such as varying transmission rates and the presence of asymptomatic carriers. By applying this model to COVID-19 data from India (30 January 2020 to 24 November 2020), chosen to capture the initial outbreak and subsequent waves, we calculate a basic reproduction number of 2.147, indicating the high transmissibility of the virus during this period in India. A sensitivity analysis reveals the critical impact of detection rates and isolation measures on disease progression, showing the robustness of our model in estimating the basic reproduction number. Through optimal control simulations, we demonstrate that increasing isolation rates for unreported cases and enhancing detection reduces the spread of COVID-19. Furthermore, our cost-effectiveness analysis establishes that a combined strategy of isolation and treatment is both more effective and economically viable. This research offers novel insights into the efficacy of non-pharmaceutical interventions, providing a tool for strategizing public health interventions and advancing our understanding of infectious disease dynamics.

Study of the Six-Compartment Nonlinear COVID-19 Model with the Homotopy Perturbation Method

The current study aims to utilize the homotopy perturbation method (HPM) to solve nonlinear dynamical models, with a particular focus on models related to predicting and controlling pandemics, such as the SIR model. Specifically, we apply this method to solve a six-compartment model for the novel coronavirus (COVID-19), which includes susceptible, exposed, asymptomatic infected, symptomatic infected, and recovered individuals, and the concentration of COVID-19 in the environment is indicated by S(t), E(t), A(t), I(t), R(t), and B(t), respectively. We present the series solution of this model by varying the controlling parameters and representing them graphically. Additionally, we verify the accuracy of the series solution (up to the (n−1)th-degree polynomial) that satisfies both the initial conditions and the model, with all coefficients correct at 18 decimal places. Furthermore, we have compared our results with the Runge–Kutta fourth-order method. Based on our findings, we conclude that the homotopy perturbation method is a promising approach to solve nonlinear dynamical models, particularly those associated with pandemics. This method provides valuable insight into how the control of various parameters can affect the model. We suggest that future studies can expand on our work by exploring additional models and assessing the applicability of other analytical methods.

A New Epidemic Model for the COVID-19 Pandemic: The θ-SI(R)D Model

Since the beginning of the COVID-19 pandemic, a large number of epidemiological models have been developed. The principal objective of the present study is to provide a new six-compartment model for the COVID-19 pandemic, which takes into account both the possibility of re-infection and the differentiation between asymptomatic and symptomatic infected subjects. The model, denoted as θ-SI(R)D, is a six-compartment model, described by as many ordinary differential equations. The six compartments are denoted as Susceptible (S), Symptomatic Infected (Is), Asymptomatic Infected (Ia), Recovered from Asymptomatic fraction (Ra), Recovered from Symptomatic fraction (Rs), and Deceased (D). Such a model has no analytical solutions, so we performed both a simulation and a model validation (R2=0.829). Based on the results of our simulations (and, on the other hand, on the results of most of the models in the scientific literature), it is possible to draw the reasonable conclusion that the epidemic tends, even without vaccination, to a steady state.

Meropenem Population Pharmacokinetics and Simulations in Plasma, Cerebrospinal Fluid, and Brain Tissue.

Meropenem is a broad spectrum carbapenem used for the treatment of cerebral infections. There is a need for data describing meropenem pharmacokinetics (PK) in the brain tissue to optimize therapy in these infections. Here, we present a meropenem PK model in the central nervous system and simulate dosing regimens. This was a population PK analysis of a previously published prospective study of patients admitted to the neurointesive care unit between 2016 and 2019 who received 2 g of meropenem intravenously every 8 h. Meropenem concentration was determined in blood, cerebrospinal fluid (CSF), and brain microdialysate. Meropenem was described by a six-compartment model: two compartments in the blood, two in the CSF, and two in the brain tissue. Creatinine clearance and brain glucose were included as covariates. The median elimination rate constant was 1.26 h-1, the central plasma volume was 5.38 L, and the transfer rate constants from the blood to the CSF and from the blood to the brain were 0.001 h-1 and 0.02 h-1, respectively. In the first 24 h, meropenem 2 g, administered every 8 h via intermittent and extended infusions achieved good target attainment in the CSF and brain, but continuous infusion (CI) was better at steady-state. Administering a 3 g loading dose (LD) followed by 8 g CI was beneficial for early target attainment. In conclusion, a meropenem PK model was developed using blood, CSF, and brain microdialysate samples. An 8 g CI may be needed for good target attainment in the CSF and brain. Giving a LD prior to the CI improved the probability of early target attainment.

Modelling and Analyzing the Potential Controls for Neospora caninum Infection in Dairy Cattle Using an Epidemic Approach

Neospora caninum (N. caninum) infection, one of the major causes of abortions in dairy cattle, has brought a huge loss to farmers worldwide. In this study, we develop a six-compartment susceptible-infected model of N. caninum transmission which is later reduced to a two-equation system. Potential controls including medication, test-and-cull, and vaccination are proposed and analyzed, and the corresponding reproduction numbers are derived. The conditions for the global stabilities of disease-free and endemic equilibria are investigated with analytical solutions and geometric approach. Furthermore, uncertainty and sensitivity analysis shows that three control strategies are effective towards the varied environment, whereas the effectiveness of each measure highly depends on parameters related to control actions. Dynamics of reproduction numbers illustrate that disease elimination can be achieved by three types of controls: (1) adopting medication with medicine efficacy higher than 0.4 to prevent vertical transmission, (2) implementing test-and-cull with culling coverage larger than 0.3, and (3) taking vaccine with coverage larger than 0.1. Numerical results suggest that preventive measures should at least include the prevention of access of other hosts, such as dogs, to cattle; otherwise, these control measures will lose effectiveness. Our presented study provides guidance for decision-making on N. caninum infected farm management.

Physiologically Based Pharmacokinetic Model for the Biotransportation of Arsenic in Marine Medaka (Oryzias melastigma).

The toxicity of arsenic (As) targets specific tissues of organisms, while the biotransportation of As among the tissues of fish remains poorly understood. In the present study, radiotracer techniques followed by a physiologically based pharmacokinetic (PBPK) modeling were applied to simulate the biotransportation (absorption, distribution, and elimination) of 73As(V) and biotransformation of As(V) in the marine medaka Oryzias melastigma after waterborne As exposure. Fish were simulated by a six-compartment model by assuming that blood was the intermediate exchange among different compartments (gill, intestine, liver, head, and carcass). Modeling suggested that intestine and gill were the uptake, exchange, as well as elimination sites of waterborne As, while carcass and head were the main storage sites. Intestine played a vital role in the metabolism of As(V) by biotransforming inorganic As into arsenobetaine (AsB), possibly because of the important role of gut microbiota. The correlation between the PBPK model constants and the As speciation (e.g., AsB %, inorganic As %, and methylated As %) indicated that AsB tended to be stored in the tissues rather than being depurated, while inorganic and methylated As were more easily transferred from tissues to the blood and eliminated. Modeling simulation coupling with biotransformation for the first time demonstrated that the fish intestine was the main metabolic site, and synthesis of AsB as mediated by the microbiota in the intestine contributed to the high As bioaccumulation in marine fish.

BIOKINETIC MODEL OF Tc-99m MIBI FOR EIGHT PATIENTS UNDERGONE MYOCARDIAL PERFUSION EXAMINATION via GAMMA CAMERA AND MATLAB PROGRAM: AN IN-VIVO STUDY

Biokinetic model of Tc-99m MIBI for eight patients undergone myocardial perfusion examination was studied using gamma camera and MATLAB program. A six-compartment model was adopted to interpret the metabolic mechanism of each patient. Within the model framework, the respective set of simultaneous differential equations was solved by a self-developed program run in MATLAB. The experimental results exhibited a good fit with the theoretical predictions via the model. The average biological half-lives of body fluid, heart, thyroid, liver, GI Tract and remainder were assessed as [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], and [Formula: see text][Formula: see text]h, respectively. A dimensionless AT index of disagreement between the experimental data and MATLAB optimal solution was proposed of validating the applied acquisition system and analytical method feasibility. An AT of zero implies a perfect agreement between the theoretical and empirical results, while averages of the derived AT were fluctuated from 3 [Formula: see text] 2 to [Formula: see text] for five compartments. The proposed refined equation estimated the internal dose from gamma-ray as [Formula: see text][Formula: see text]mSv for eight patients according to a fast screening method, which defined human body as a spherical ball to simplify the calculation in reality. The proposed MATLAB-based fitting of in-vivo data with the theoretical results was instrumental for assessing the radiation dose received by the Tc-99m MIBI scan participants.

Homeostatic regulation of copper in a marine fish simulated by a physiologically based pharmacokinetic model

Copper (Cu) is an essential yet potentially toxic metal, thus delicate homeostatic controls are developed in the fish. In this study, a physiologically based pharmacokinetic (PBPK) model was developed to simulate the homeostatic regulation of Cu in a marine fish (Terapon jarbua) under dietary and waterborne exposures. In this model, fish were schematized as a six-compartment model, with the intestine being divided into two sub-compartments (chyme and gut wall). The blood was assumed to be the “carrier” distributing Cu into different compartments. The transfer rates between different compartments were determined in fish during Cu exposure (20 d) and depuration (20 d). The differences in Cu transfer from chyme to gut wall between dietary and waterborne treatments suggested that the intestine regulated the dietary uptake and re-absorption of Cu from the chyme. The extremely low uptake rate constant (0.0013 d−1) for gills under waterborne exposure indicated that gills strongly restricted Cu uptake from the ambient water. For both treatments, the liver had considerable input rate through the enterohepatic circulation and comparably high exchange rate with the blood, suggesting that the liver can efficiently accumulate newly absorbed Cu. The differences in Cu output from the liver between dietary and waterborne treatments suggested that it can effectively regulate the redistribution of Cu. All of these observations demonstrated that the liver played the central role in Cu homeostasis by serving as the main depository and distributing center. Modeling results also indicated that renal and branchial excretion was of minor importance, whereas biliary excretion combined with defecation played the most important role in whole-body Cu elimination in marine fish. The effective regulation by the “Blood-Liver-Intestine” cycle could be the main reason for the relatively low levels of Cu in fish.

Physiologically Based Pharmacokinetic Model for Inorganic and Methylmercury in a Marine Fish

A physiologically based pharmacokinetic (PBPK) model was developed to simulate the uptake, distribution, and elimination of inorganic mercury [Hg(II)] and methylmercury (MeHg) in a marine fish, Terapon jarbua. In this model, fish were schematized as a six-compartment model by assuming that blood was the medium linking the exchange between the different compartments. The transfer rates between blood and other compartments were determined during a period of 10-day dietary Hg(II) or MeHg exposure, followed by a 30-day depuration. For both Hg species, the exchange rates between liver and blood were high, indicating that liver served as a "transferring station" in the distribution. Their accumulation in the kidney was relatively constant and low. The carcass (mainly muscle) represented a large sink for both Hg(II) and MeHg with the highest input rate constants and relatively lower output rate constants. Significant differences were observed in the rate constants between the two Hg species, suggesting great variations in their exchange and transportation routes. Modeling simulation for the first time demonstrated that the gill was the most important route in Hg(II) elimination in marine fish, with a rate constant of 0.90 d(-1). A long time frame is needed to study the exact rate of MeHg elimination in marine fish. This study showed that the PBPK modeling provided critical information for the uptake, distribution and elimination of Hg(II) and MeHg in the fish body, especially in elucidating the role of each compartment.

Modeling of hyaluronan clearance with application to estimation of lymph flow

One of the important factors in blood pressure regulation is the maintenance of the level of blood volume, which depends on several factors including the rate of lymph flow. Lymph flow can be measured directly using cannulation of lymphatic vessels, which is not clinically feasible, or indirectly by the tracer appearance rate, which is the rate at which macromolecules appear into the blood from the peritoneal cavity. However, indirect lymph flow measurements do not always provide consistent results. Through its contribution to osmotic pressure and resistance to flow, the macromolecule hyaluronan takes part in the regulation of tissue hydration and the maintenance of water and protein homeostasis. It arrives in blood plasma through lymph flow. Lymphatic hyaluronic acid (HA, hyaluronan) concentration is several times higher than that in plasma, suggesting that the lymphatic route may account for the majority of HA found in plasma. Furthermore, circulating levels of HA reflect the dynamic state between delivery to—and removal from—the bloodstream. To develop an accurate estimation of the fluid volume distribution and dynamics, the rate of lymph flow needs to be taken into account and hyaluronan could be used as a marker in estimating this flow. To examine the HA distribution and system fluid dynamics, a six-compartment model, which could reflect both the steady-state relationships and qualitative characteristics of the dynamics, was developed. This was then applied to estimate fluid shifts from the interstitial space via the lymphatic system to the plasma during different physiological stresses (orthostatic stress and the stress of ultrafiltration during dialysis). Sensitivity analysis shows that during ultrafiltration, lymph flow is a key parameter influencing the total HA level, thus suggesting that the model may find applications in addressing the problem of estimating lymph flow. Since the fluid balance between interstitium and plasma is maintained by lymph flow and microvasculature filtration, our novel method of flow estimation may provide an important tool for understanding fluid dynamics during perturbations of the cardiovascular system. Since the fluid balance between interstitium and plasma is maintained by lymph flow and microvasculature filtration, our novel method of flow estimation may provide an important tool for understanding fluid dynamics during perturbations of the cardiovascular system.

Energetics of Inhibition: Insights with a Computational Model of the Human GABAergic Neuron–Astrocyte Cellular Complex

We investigate metabolic interactions between astrocytes and GABAergic neurons at steady states corresponding to different activity levels using a six-compartment model and a new methodology based on Bayesian statistics. Many questions about the energetics of inhibition are still waiting for definite answers, including the role of glutamine and lactate effluxed by astrocytes as precursors for γ-aminobutyric acid (GABA), and whether metabolic coupling applies to the inhibitory neurotransmitter GABA. Our identification and quantification of metabolic pathways describing the interaction between GABAergic neurons and astrocytes in connection with the release of GABA makes a contribution to this important problem. Lactate released by astrocytes and its neuronal uptake is found to be coupled with neuronal activity, unlike glucose consumption, suggesting that in astrocytes, the metabolism of GABA does not require increased glycolytic activity. Negligible glutamine trafficking between the two cell types at steady state questions glutamine as a precursor of GABA, not excluding glutamine cycling as a transient dynamic phenomenon, or a prominent role of GABA reuptake. Redox balance is proposed as an explanation for elevated oxidative phosphorylation and adenosine triphosphate hydrolysis in astrocytes, decoupled from energy requirements.

A software supported compartmental modeling approach for Paenibacillus polymyxa

This paper shows the derivation, selection and validation of a six-compartment model for P. polymyxa fed-batch fermentations on minimal media. P. polymyxa is known to produce a highly potent antibiotic, namely macrolactin. While biological insight is exploited to set up a basic model structure, a modeling tool is used to automatically select between possible reaction rates to describe individual steps. Experiments are used to identify the model parameters, and the most promising model candidate is validated with another experiment.

Population Pharmacokinetics of 3,4-Methylenedioxymethamphetamine and Main Metabolites in Rats

The pharmacokinetics of the recreational drug 3,4-methylenedioxymethamphetamine (MDMA) and its mains metabolites have never been modeled together. We therefore designed a model with which to analyze the pharmacokinetics of MDMA, 3,4-methylenedioxyamphetamine (MDA), 4-hydroxy-3-methoxymethamphetamine (HMMA), and 4-hydroxy-3-methoxyamphetamine (HMA) and to test the effect of covariates like gender and body weight on the pharmacokinetics. Rats (18 males and 18 females) were given 1 mg/kg MDMA iv, and the concentrations of MDMA, MDA, and HMMA were measured by high-performance liquid chromatography-mass spectrometry. Another 30 rats (15 males) were given 1 mg/kg MDA, and MDA and HMA were measured. A population pharmacokinetic model was developed to describe the changes in MDMA, HMMA, MDA, and HMA concentrations over time and to estimate interanimal variability. The influence of gender was tested using a likelihood ratio test. Estimated exposures of males and females to MDMA and its metabolites were compared using the Wilcoxon nonparametric test. An integrated six-compartment model adequately described the data. MDMA (two compartments) was transformed irreversible to HMMA (one compartment) and MDA (two compartments), which then produced HMA (one compartment). All rate constants were first order. Females given MDMA had significantly smaller MDMA distribution volumes than males, and they converted less MDMA to MDA than did males. Our MDMA, MDA, HMA, and HMMA model is suitable for examining the relationship between drug concentrations and its pharmacological/toxicological effects. Male rats were exposed to significantly more MDA and HMA than were females, which could explain why males are more sensitive to MDMA toxic effects than females.

AQUAVAN® Injection, a Water-soluble Prodrug of Propofol, as a Bolus Injection: A Phase I Dose-escalation Comparison with DIPRIVAN® (Part 1): Pharmacokinetics: Retracted

AQUAVAN Injection (AQ) (GPI 15715; Guilford Pharmaceutical Inc., Baltimore, MD) is a water-soluble prodrug of propofol (PropofolGPI). This study aimed to explore the pharmacokinetics of AQ, PropofolGPI, and formate (a metabolite of AQ) and to compare them with the pharmacokinetics of propofol lipid emulsion (PropofolD). After ethics committee approval, 36 healthy volunteers were randomly allocated into six cohorts (male/female: 3/3) and given a single bolus of AQ (5, 10, 15, 20, 25, or 30 mg/kg). For comparison, an equipotent dose (as measured by the Bispectral Index) of PropofolD was given to the same subjects 1 week later. For both drugs, blood samples were collected (1-480 min) to analyze AQ, PropofolGPI, PropofolD, and formate concentrations. Noncompartmental pharmacokinetic analyses were performed for all analytes. A population compartmental model was developed for AQ and PropofolGPI using NONMEM. The models were evaluated using simulations and bootstraps. The noncompartmental pharmacokinetic comparison revealed different dispositions of PropofolGPI and PropofolD. The maximum plasma concentration was lower for PropofolGPI than for PropofolD at equipotent doses, and apparent clearance and distribution volume were much higher for PropofolGPI than for PropofolD. Formate concentrations were similar when injecting both drugs and were not higher than baseline. Compartmental modeling revealed that the pharmacokinetic behavior of AQ and its liberated PropofolGPI was best described by a nonlinear, six-compartment model, composed of two three-compartment models connected to each other by hydrolysis of AQ to PropofolGPI. PropofolGPI showed different noncompartmental pharmacokinetics from PropofolD, hereby revealing the influence of the formulation. The combined model for AQ and PropofolGPI was best modeled by a nonlinear, six-compartment model.

Population pharmacokinetic modeling of blood-brain barrier transport of synthetic adenosine A1 receptor agonists.

A population pharmacokinetic model is proposed for estimation of the brain distribution clearance of synthetic A1 receptor agonists in vivo. Rats with permanent venous and arterial cannulas in combination with a microdialysis probe in the striatum received intravenous infusions of 8-methylamino-N6-cyclopentyladenosine (MCPA) and 2'-deoxyribose-N6-cyclopentyladenosine (2'-dCPA) (10 mg kg(-1)). The clearance for transport from blood to the brain was estimated by simultaneous analysis of the blood and extracellular fluid concentrations using a compartmental pharmacokinetic model. The proposed pharmacokinetic model consists of three compartments describing the time course of the concentration in blood in combination with three compartments for the brain extracellular fluid concentrations. The blood clearance was 7.4 +/- 0.5 for MCPA and 7.2 +/- 1.4 ml min(-1) for 2'-dCPA. The in vivo microdialysis recoveries determined by the dynamic-no-net-flux method were independent of time with values of 0.21 +/- 0.02 and 0.22 +/- 0.01 for MCPA and 2'-dCPA, respectively. The values of the intercompartmental clearance for the distribution from blood to brain were 1.9 +/- 0.4 versus 1.6 +/- 0.3 mul min(-1) for MCPA and 2'-dCPA, respectively. It is concluded that on basis of the novel six-compartment model precise estimates of the rate of brain distribution are obtained that are independent of eventual differences in systemic exposure. The low brain distribution rates of MCPA and 2'-dCPA were consistent with in vitro tests. Furthermore, a slow elimination from the brain compartment was observed, indicating that the duration of central nervous system effects may be much longer than expected on the basis of the terminal half-life in blood.

Estimation of intradermal disposition kinetics of drugs: II. Factors determining penetration of drugs from viable skin to muscular layer

To develop a more efficient transdermal delivery system, it is very important to regulate the intradermal disposition of drugs after topical application. We tried to elucidate the factors determining the intradermal disposition kinetics, especially drug penetration from the viable skin to the muscular layer, mainly based on the six-compartment model, including the contralateral skin and muscle for ten model drugs with different physicochemical characteristics. In vivo transdermal absorption study was performed for six model drugs using the stripped-skin rats. The fitting analyses by the six-compartment model gave the theoretical curves describing the observed data very well and the reasonable pharmacokinetic parameters, showing the pharmacokinetic model should be useful for the estimation of the intradermal disposition kinetics of drugs applied topically again. The simulation study using the pharmacokinetic parameters obtained above could show the relative contribution of the direct penetration and the distribution from the systemic circulation to the muscular distribution of drugs. The largest contribution of direct penetration was observed for antipyrine (90.8%) and the smallest was for felbinac (43.3%). Among the pharmacokinetic parameters obtained above, the clearance from the viable skin to the muscle ( CL vs–m) was found to be significantly correlated with the unbound fraction of drugs in the viable skin ( fu vs). Although the clearance from the viable skin to the plasma ( CL vs–p) also tended to increase as fu vs increased, the ratio of CL vs–m to CL vs–p was significantly correlated with fu vs, meaning that the larger amount of unbound drug in the viable skin significantly contributes to the direct penetration into the muscle more than to the systemic absorption. On the other hand, k direct values obtained in in vitro penetration study—the penetration rate constant of drugs from the viable skin to the muscular layer—were found to be correlated with CL vs–m values for seven model drugs. Therefore, adding the in vitro experiments for the other three model drugs, the multiple linear regression analysis of k direct was performed for ten model drugs in terms of fu vs, logarithm of the partition coefficient (Log P) and molecular weight. The results clearly showed the largest and significant contribution of fu vs to the direct penetration of drugs from the viable skin to the muscular layer, indicating that a drug with the higher value of fu vs in the viable skin can penetrate more into the muscular layer.

EVALUATION OF SYSTEM PERFORMANCE THROUGH OPTIMIZING ASCENDENCY IN AN AQUATIC ECOSYSTEM MODEL

We develop a six-compartment model consisting of phosphorus, detritus, phytoplankton, zooplankton, planktonivorous fish and pisciphagous fish. In this model, we study the implications that the body sizes of phytoplankton and zooplankton have on the system dynamics. We use ascendency as a goal function or indicator of system performance. Ascendency quantifies growth and development of an ecosystem as a product of total system throughflow and the mutual information inherent in the pattern of internal system flows. Different physiological rate parameters of phytoplankton and zooplankton are assessed by means of allometric relationships applied to their body sizes. We let the phytoplankton body size range from 10 μm3to 107μm3and the zooplankton body size range from 10 μm3to 104μm3in volume. We also investigate the effects of phosphorus input conditions, corresponding to oligotrophic, mesotrophic and eutrophic systems on system dynamics. Ascendency (to be maximized over phytoplankton and zooplankton sizes) was computed after the system had reached a steady state. Since it always was a seasonal cycle, and the ascendency followed this behavior, we averaged the ascendency over 365 successive days (duration of one year) in the oscillatory phase. Under all types of nutrient conditions, the smallest phytoplankton size yielded the maximal values of the ascendency, while the corresponding zooplankton size varied. Under oligotrophic conditions, a phytoplankton size of 10 μm3combined with a zooplankton size of 101.25μm3to give the maximum value of the ascendency. Under mesotrophic and eutrophic conditions, maxima were obtained for zooplankton sizes 102.26μm3and 103.20μm3, respectively.

Body Weight-Specific Zinc Compartmental Masses in Girls Significantly Exceed Those Reported in Adults: A Stable Isotope Study Using a Kinetic Model

Maintaining optimal zinc status is important for normal growth and development in children, but minimal data are available regarding zinc metabolism in this age group. Our objectives were to utilize stable isotope-based compartmental modeling techniques to investigate zinc metabolism in healthy children; to expand a current stable isotope-based model to include red blood cell data; and to compare kinetic parameters in children with those previously reported in adults. Seven healthy girls, age 9.94 +/- 0.79 y, received 1.1 mg of a (67)zinc-enriched tracer orally and 0.5 mg of a (70)zinc-enriched tracer intravenously. Blood, urine and fecal samples were collected for 6 d. Stable isotope enrichments were measured by thermal ionization magnetic sector mass spectrometry. A six-compartment model based on a model previously reported in adults was used; the model excluded red blood cell data. Body weight-corrected masses of the body zinc compartments derived using this model were significantly greater in children than those reported in adults. Modification of the model to include a red blood cell compartment increased the total identifiable zinc mass of the nongastrointestinal compartments by approximately 2.5%. We conclude that compartmental modeling can be used to describe zinc kinetics in children, and that the body weight-corrected zinc pool masses are significantly greater in children than in adults.

A Comprehensive Model for Enrofloxacin to Ciprofloxacin Transformation and Disposition in Dog

□ The pharmacokinetics of enrofloxacin and ciprofloxacin, its major active metabolite, were determined in dog after oral and intravenous administrations of enrofloxacin and intravenous infusion of ciprofloxacin. A comprehensive model of enrofloxacin and ciprofloxacin disposition was constructed to investigate the extent of enrofloxacin to ciprofloxacin transformation and the influence of the hepatic first-pass effect on the parent compound oral bioavailability. Plasma levels were measured using a validated HPLC method. Enrofloxacin and ciprofloxacin plasma concentration data were fitted simultaneously using a set of differential equations describing a six-compartment model (two compartments for each analyte, one for the liver, and one for the intestinal tract); it was assumed that only a fraction of enrofloxacin was metabolized to ciprofloxacin and that this conversion only occurred in the liver. The fitted parameters obtained from the model were used to calculate plasma clearances (0.729±0.212L/h/kg for enrofloxacin, 0.468±0.094L/h/kg for ciprofloxacin), distribution volumes (2.45±0.49L/kg for enrofloxacin, 1.92±0.33L/kg for ciprofloxacin), mean residence times (3.47±0.78h for enrofloxacin, 4.20±0.82h for ciprofloxacin), and the fractions of enrofloxacin metabolized to ciprofloxacin after intravenous and oral administrations of enrofloxacin. it was shown that enrofloxacin was largely metabolized to ciprofloxacin and that the fractions of metabolized enrofloxacin were similar after intravenous and oral administrations of enrofloxacin (40.44±10.08 and 40.17±8.33%, respectively), the hepatic first-pass effect being low (7.15±1.99%).

A regional chemical fate and exposure model suitable for Denmark and its coastal sea

A generic screening level model for the regional environmental fate and exposure of industrial organic chemicals has been developed for Denmark and its coastal sea. The model is a further development of a European generic model proposed by the Commission of the European Union (EU) for use in chemical risk assessment. The EU model is a “Mackay-type” level III model with four compartments: air, soil, freshwater and freshwater sediments. To better represent the geography of Denmark that consists of islands and a peninsula a six-compartment model was constructed by adding a seawater compartment and a marine sediment compartment to the standard EU-model. To obtain a realistic mean hydraulic retention time of freshwater, the freshwater compartment was reduced to represent lakes only, treating emissions to rivers downstream lakes as emissions directly to the sea. The sea compartment was confined to the transition between the Baltic and the North Sea that receives the major part of the Danish wastewater discharges and is a physically well-defined entity. Case studies with lindane, chloroform, pentachlorophenol (PCP), hexachlorobenzene, linear alkyl benzene sulphonates (LAS), 1-dodecanol, and trichlorethylene (TCE) demonstrated that in scenarios with significant local waterborn emission of volatile compounds predictions with the six compartment model could be significantly different from those obtained with the standard EU model. For LAS, lindane, PCP, TCE and chloroform, limited sets of available monitoring data were in fair agreement with model predictions. A sensitivity analysis showed among others that the local emissions as well as the imports across the model boundary were important determinants. A tentative risk assessment based on regional PEC (predicted environmental concentration)/PNEC (predicted no effect concentration) ratios indicated that there should be no environmental risk at the regional scale for chloroform, PCP, and TCE in Denmark. For LAS the calculated PEC/PNEC ratios were between 2–18% for soil, water and sediment when EU standard assessment factors were used to estimate the PNEC.