Bicarbonate kinetics in humans: identification and validation of a three-compartment model

1995 ◽  
Vol 269 (1) ◽  
pp. E183-E192 ◽  
Author(s):  
M. P. Saccomani ◽  
R. C. Bonadonna ◽  
E. Caveggion ◽  
R. A. DeFronzo ◽  
C. Cobelli
Keyword(s):  
Specific Activity ◽  
Model Identification ◽  
Compartment Model ◽  
Central Compartment ◽  
Good Evidence ◽  
The Body ◽  
Endogenous Production ◽  
Three Compartment Model ◽  
Expired Air

A model of bicarbonate kinetics is crucial to a correct interpretation of experiments for measuring oxidation in vivo of carbon-labeled compounds. The aim of this study is to develop a compartmental model of bicarbonate kinetics in humans from tracer data by devoting particular attention to model identification and validation. The data base consisted of impulse-dose studies of 14C-labeled bicarbonate in nine normal subjects. The decay curve of specific activity of CO2 in expired air (saRCO2) was frequently sampled for 4-7 h. In addition, endogenous production of CO2, VCO2, was measured by indirect calorimetry. A model of data, i.e., an exponential model, analysis of decay curves of saRCO2 showed first that three compartments are necessary and sufficient to describe bicarbonate tracer kinetics. Compartmental models were then used as models of system. To correctly describe the input-output configuration, labeled CO2 flux in the expired air, phi RCO2 (= saRCO2.VCO2), has been used as measurement variable in tracer model identification. A mammillary three-compartment model with a respiratory and a nonrespiratory loss has been studied. Whereas there is good evidence that respiratory loss takes place in the central compartment, whether nonrespiratory loss is taking place in the central compartment or in one of the two peripheral compartments is uncertain. Thus three competing tracer models were considered. Using a model-independent analysis of data, based on the body activity variable, to calculate mean residence time in the system, we have been able to validate a specific model structure, i.e., with the two irreversible losses taking place in the central compartment. This validated tracer model was then used to quantitate bicarbonate masses in the system. Because there is uncertainty about where endogenous production enters the system, lower and upper bounds of masses of bicarbonate in the body are derived.

Theory of production rate calculations in steady and non-steady states and its application to glucose metabolism

1992 ◽  
Vol 262 (6) ◽  
pp. E779-E790 ◽  
Author(s):  
J. A. Jacquez
Keyword(s):  
Steady State ◽  
Experimental Design ◽  
Specific Activity ◽  
Glucose Production ◽  
Central Compartment ◽  
Correct Equation ◽  
Endogenous Production ◽  
Correction Terms ◽  
Theory Of Production ◽  
Constant Specific Activity

I present a review and synthesis of the basic theory, steady state, and non-steady state for the calculation of metabolite production rates for systems that have a central well-mixed compartment that is the site of tracer input and sampling. The theory is then applied to the calculation of glucose production. If the only inputs are into the central compartment, an experimental design that involves varying tracer infusion rates to maintain constant specific activity in the central compartment and the same constant specific activity in the peripheral compartments allows calculation of the endogenous production. That holds even if the models are unidentifiable. The correct equation and Steele's pool fraction approximation reduce to the same result for this experimental design. However, that does not justify the use of Steele's equation when there are deviations from the exact experimental design. When the specific activity in the central compartment is not constant, model-dependent correction terms to Steele's equation are needed.

Allopurinol kinetics in humans as a means to assess liver function: comparison of different models

1987 ◽  
Vol 253 (2) ◽  
pp. R352-R360 ◽  
Author(s):  
G. van Waeg ◽  
T. Groth ◽  
F. Niklasson ◽  
C. H. de Verdier
Keyword(s):  
Liver Function ◽  
Intravenous Injection ◽  
Healthy Subjects ◽  
Tight Binding ◽  
Compartment Model ◽  
Central Compartment ◽  
Fractional Rate ◽  
Computer Based ◽  
Loading Tests ◽  
Three Compartment Model

To describe the mechanisms involved in allopurinol kinetics after intravenous injection in humans, a number of alternative computer-based biodynamic models were designed. Distribution processes were described with two-compartment as well as with three-compartment kinetics for both allopurinol and its metabolite oxipurinol. These two major physiological alternatives were combined with biochemical models assuming either competitive or tight-binding-complex inhibition kinetics. The four resulting basic models were evaluated (and successively improved) using sets of plasma allopurinol and oxipurinol concentration curves, measured after intravenous injection in healthy subjects and in patients with different degrees of liver function. A three-compartment model with tight-binding-complex inhibition was selected and used to analyze the 35 loading tests performed. One of the parameters estimated in this way, the fractional rate constant for transport of allopurinol from the central compartment to the metabolically active (liver) compartment (kA31), turned out to be a powerful discriminative parameter between a group of healthy subjects, a group of patients with slightly to moderately reduced overall liver function, and a group with severely reduced overall liver function [kA31(min-1) = 0.136 +/- 0.042 (mean +/- SD, n = 13), 0.072 +/- 0.024 (n = 13), and 0.025 +/- 0.015 (n = 8), respectively].

scholarly journals The role of endoplasmic reticulum in in vivo cancer FDG kinetics

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0252422
Author(s):  
Sara Sommariva ◽  
Mara Scussolini ◽  
Vanessa Cossu ◽  
Cecilia Marini ◽  
Gianmario Sambuceti ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cancer Metabolism ◽  
Cultured Cells ◽  
Accumulation Rate ◽  
Compartment Model ◽  
Compartment System ◽  
Positron Emission Tomography Scanner ◽  
Three Compartment Model

A recent result obtained by means of an in vitro experiment with cancer cultured cells has configured the endoplasmic reticulum as the preferential site for the accumulation of 2-deoxy-2-[18F]fluoro-D-glucose (FDG). Such a result is coherent with cell biochemistry and is made more significant by the fact that the reticular accumulation rate of FDG is dependent upon extracellular glucose availability. The objective of the present paper is to confirm in vivo the result obtained in vitro concerning the crucial role played by the endoplasmic reticulum in FDG cancer metabolism. This study utilizes data acquired by means of a Positron Emission Tomography scanner for small animals in the case of CT26 models of cancer tissues. The recorded concentration images are interpreted within the framework of a three-compartment model for FDG kinetics, which explicitly assumes that the endoplasmic reticulum is the dephosphorylation site for FDG in cancer cells. The numerical reduction of the compartmental model is performed by means of a regularized Gauss-Newton algorithm for numerical optimization. This analysis shows that the proposed three-compartment model equals the performance of a standard Sokoloff’s two-compartment system in fitting the data. However, it provides estimates of some of the parameters, such as the phosphorylation rate of FDG, more consistent with prior biochemical information. These results are made more solid from a computational viewpoint by proving the identifiability and by performing a sensitivity analysis of the proposed compartment model.

A minimal model for human whole body cholesterol metabolism

1993 ◽  
Vol 265 (3) ◽  
pp. E513-E520
Author(s):  
R. E. Ostlund
Keyword(s):  
Minimal Model ◽  
Cholesterol Metabolism ◽  
Specific Activity ◽  
Clinical Investigation ◽  
Plasma Cholesterol ◽  
Fractional Excretion ◽  
Compartment Model ◽  
The Body ◽  
Whole Body ◽  
Mean Values

Important work by others has shown that human whole body cholesterol metabolism can be described by a three-compartment model computed from plasma cholesterol specific activity after an intravenous infusion of labeled cholesterol. However, some parameters of that model cannot be estimated precisely [coefficient of variation (CV) 15-19% after 40 wk of follow-up], making its use in routine clinical investigation difficult. On the other hand, a simpler two-compartment model can be calculated with excellent precision from only 10 wk of data (CV 2-8%), but its parameters are inaccurate (for example, the size of the central pool is overestimated by 20%, and the rate constant for fractional excretion of cholesterol from the body is underestimated by 15%). Thus both three-compartment and two-compartment models of cholesterol turnover have important limitations. An alternative is provided by a minimal model that takes advantage of the increased precision expected in the solution of models with fewer parameters. A three-compartment structure is used, but only four (rather than 6 or more) parameters are calculated: the mass of the rapidly mixing central cholesterol compartment, the fractional rate of cholesterol elimination from the body, and the average forward and reverse rate constants for cholesterol transfer between the rapid compartment and both slower compartments. Each of these parameters can be determined unambiguously (without the need to use a minimum or maximum estimate), accurately (mean values within 2% of theory), and with precision (CV 3-13%).(ABSTRACT TRUNCATED AT 250 WORDS)

THE SPECIFIC ACTIVITY OF PLASMA CORTISOL IN SHEEP AFTER INTRAVENOUS INFUSION OF [1,2-3H2]CORTISOL, AND ITS RELATION TO THE DISTRIBUTION OF CORTISOL

1968 ◽  
Vol 40 (1) ◽  
pp. 37-47 ◽  
Author(s):  
J. Y. F. PATERSON ◽  
F. A. HARRISON
Keyword(s):  
Intravenous Infusion ◽  
Plasma Cortisol ◽  
Specific Activity ◽  
Compartment Model ◽  
Central Compartment ◽  
Cortisol Concentration ◽  
Two Compartment Model ◽  
Outer Compartment ◽  
Constant Rate ◽  
Near Term

SUMMARY Tritium-labelled cortisol was administered to sheep by intravenous infusion at constant rate for up to 4 hr. When the infusion was stopped, [3H] cortisol disappeared rapidly from plasma and its concentration could be described by a double exponential function. There was good agreement between the results from 50 experiments on 11 sheep. In pregnant ewes, there was no noticeable difference in the rate of disappearance of [3H]cortisol from plasma until about 2 weeks before lambing, when the rate became more rapid. These data were interpreted in terms of a two-compartment model of cortisol distribution. The central compartment contains about 42 μg. cortisol and may be identical with the cortisol contained in whole blood volume. The outer compartment contains about 130 μg. cortisol; less than half of this compartment may be in intercellular fluids, partly bound to protein, and the remainder in intracellular fluids. In pregnant ewes near term there is a decrease in plasma cortisol concentration which appears to result from expansion of plasma volume. The decrease in unbound cortisol concentration probably results in a decrease in the size of the outer compartment of cortisol. This may contribute to the observed increase in the rate of disappearance of [3H] cortisol from plasma, but this change may also coincide with the initiation of secretion of cortisol by the foetus, at about 1 or 2 μg./min.

Population Pharmacokinetics of Propofol

2000 ◽  
Vol 92 (3) ◽  
pp. 727-738 ◽  
Author(s):  
Jürgen Schüttler ◽  
Harald Ihmsen
Keyword(s):  
San Francisco ◽  
Sampling Site ◽  
Compartment Model ◽  
Central Compartment ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Power Functions ◽  
Target Controlled Infusion ◽  
Three Compartment Model ◽  
Elimination Clearance

Background Target-controlled infusion is an increasingly common type of administration for propofol. This method requires accurate knowledge of pharmacokinetics, including the effects of age and weight. The authors performed a multicenter population analysis to quantitate the effects of covariates. Methods The authors analyzed 4,112 samples of 270 individuals (150 men, 120 women, aged 2-88 yr, weighing 12-100 kg). Population pharmacokinetic modeling was performed using NONMEM (NONMEM Project Group, University of California, San Francisco, CA). Inter- and intraindividual variability was estimated for clearances and volumes. The effects of age, weight, type of administration and sampling site were investigated. Results The pharmacokinetics of propofol were best described by a three-compartment model. Weight was found to be a significant covariate for elimination clearance, the two intercompartmental clearances, and the volumes of the central compartment, the shallow peripheral compartment, and the deep peripheral compartment; power functions with exponents smaller than 1 yielded the best results. The estimates of these parameters for a 70-kg adult were 1.44 l/min, 2.25 l/min, 0.92 l/min, 9.3 l, 44.2 l, and 266 l, respectively. For patients older than 60 yr the elimination clearance decreased linearly. The volume of the central compartment decreased with age. For children, all parameters were increased when normalized to body weight. Venous data showed a decreased elimination clearance; bolus data were characterized by increases in the volumes of the central and shallow peripheral compartments and in the rapid distribution clearance (Cl2) and a decrease in the slow distribution clearance (Cl3). Conclusions Pharmacokinetics of propofol can be well described by a three-compartment model. Inclusion of age and weight as covariates significantly improved the model. Adjusting pharmacokinetics to the individual patient should improve the precision of target-controlled infusion and may help to broaden the field of application for target-controlled infusion systems.

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