scholarly journals Analysis of Time Courses of Metabolic Precursors and Products in Heterogeneous Rat Brain Tissue: Limitations of Kinetic Modeling for Predictions of Intracompartmental Concentrations from Total Tissue Activity

1995 ◽  
Vol 15 (3) ◽  
pp. 474-484 ◽  
Author(s):  
Kathleen C. Schmidt ◽  
Günter Mies ◽  
Gerald A. Dienel ◽  
Nancy F. Cruz ◽  
Alison M. Crane ◽  
...  
Keyword(s):  
Rate Constant ◽  
Kinetic Models ◽  
Goodness Of Fit ◽  
Glucose Utilization ◽  
Total Radioactivity ◽  
Tissue Heterogeneity ◽  
Metabolic Products ◽  
Product Loss ◽  
Time Courses ◽  
Total Tissue

The efficacy of various kinetic models to predict time courses of total radioactivity and levels of precursor and metabolic products was evaluated in heterogeneous samples of freeze-blown brain of rats administered [14C]deoxyglucose ([14C]DG). Two kinetic models designed for homogeneous tissues, i.e., a no-product-loss, three-rate-constant (3K) model and a first-order-product-loss, four-rate-constant (4K) model, and a third kinetic model designed for heterogeneous tissues without product loss [Tissue Heterogeneity (TH) Model] were examined. In the 45-min interval following a pulse of [14C]DG, the fit of the TH Model to total tissue radioactivity was not statistically significantly better than that of the 3K Model, yet the TH Model described the time courses of [14C]DG and its metabolites more accurately. The TH- and 4K-Model-predicted time courses of [14C]DG and its metabolites were similar. Whole-brain glucose utilization (CMRglc) calculated with the TH or 3K Model, ∼75 μmol 100 g−1 min−1, was similar to values previously determined by model-independent techniques, whereas CMRglc calculated with the 4K Model was 44% higher. In a separate group of rats administered a programmed infusion to attain a constant arterial concentration of [14C]DG that minimizes effects of tissue heterogeneity as well as any product loss, CMRglc calculated with all three models was 79 μmol 100 g−1 min−1 at 45 min after initiation of the infusion. Statistical comparisons of goodness of fit of total tissue radioactivity were, therefore, not indicative of which models best describe the tissue precursor and product pools or which models provide the most accurate rates of glucose utilization.

scholarly journals Errors Introduced by Tissue Heterogeneity in Estimation of Local Cerebral Glucose Utilization with Current Kinetic Models of the [18F]Fluorodeoxyglucose Method

1992 ◽  
Vol 12 (5) ◽  
pp. 823-834 ◽  
Author(s):  
K. Schmidt ◽  
G. Lucignani ◽  
R. M. Moresco ◽  
G. Rizzo ◽  
M. C. Gilardi ◽  
...  
Keyword(s):  
Rate Constant ◽  
Kinetic Models ◽  
Time Course ◽  
Glucose Utilization ◽  
Experimental Period ◽  
Tissue Heterogeneity ◽  
Cerebral Glucose Utilization ◽  
Positron Emission ◽  
Normal Humans ◽  
Homogeneous Tissue

The effects of tissue heterogeneity on the estimation of regional cerebral glucose utilization (rCMRglc) in normal humans with [18F]2-fluoro-2-deoxy-d-glucose ([18F]FDG) and positron emission tomography (PET) were compared with respect to the various kinetic models of the [18F]FDG method. The kinetic models were conventional homogeneous tissue models of the [18F]FDG method, with (4K Model) and without (3K Model) a rate constant to account for an apparent loss of [18F]2-fluoro-2-deoxy-d-glucose-6-phosphate ([18F]FDG-6-P), and a tissue heterogeneity model (TH Model). When either of the kinetic models designed for homogeneous tissues was applied to heterogeneous tissues, estimates of the rate constant for efflux of [18F]FDG from the tissue ( k*2) and of the rate constant for phosphorylation of [18F]FDG ( k*3) decreased as the duration of the experimental period was increased. When the 4K Model was used, estimates of the rate constant for the apparent dephosphorylation of [18F]FDG-6-P ( k*4) were significantly greater than zero and fell with increasing duration of the experimental period. Although the TH Model included no term to describe an apparent dephosphorylation of [18F]FDG-6-P, the fit of the TH Model to the time course of total tissue radioactivity was at least as good as and often better than the fit of the 4K Model in the 120-min period following the pulse of [18F]FDG. Hence, the high estimates of k*4 found in PET studies of ≤120 min can be explained as the consequence of measuring radioactivity in a heterogeneous tissue and applying a model designed for a homogeneous tissue; there remains no evidence of significant dephosphorylation of [18F]FDG-6-P in this time period. Furthermore, use of the 4K Model led to an overestimation of rCMRglc; whole-brain glucose utilization calculated with the 4K Model was >20% higher than values usually obtained in normal humans by the model-independent Kety–Schmidt technique. rCMRglc was accurately estimated by the TH Model and, in experimental periods sufficiently long to minimize the effects of tissue heterogeneity, also by the original 3K Model of the deoxyglucose method.

scholarly journals Model of Kinetic Behavior of Deoxyglucose in Heterogeneous Tissues in Brain: A Reinterpretation of the Significance of Parameters Fitted to Homogeneous Tissue Models

1991 ◽  
Vol 11 (1) ◽  
pp. 10-24 ◽  
Author(s):  
K. Schmidt ◽  
G. Mies ◽  
L. Sokoloff
Keyword(s):  
Rate Constant ◽  
Weighted Average ◽  
Effective Rate Constant ◽  
Direct Consequence ◽  
Experimental Period ◽  
Tissue Heterogeneity ◽  
Product Loss ◽  
Dg Method ◽  
Heterogeneous Tissue ◽  
Homogeneous Tissue

Effects of tissue heterogeneity on regional CMRglc (rCMRglc) calculated by use of the deoxyglucose (DG) method at 45 min following the pulse of DG were evaluated in simulation studies. A theoretical model was developed to describe the kinetics of DG uptake and metabolism in heterogeneous brain tissues. Rate constants were fitted to simulation data for mixed tissue and rCMRglc computed on the basis of this tissue heterogeneity model. The results were compared with those obtained by use of the original model of the DG method for homogeneous tissue, both without (3K model) and with (4K model) a term to describe an apparent loss of deoxyglucose-6-phosphate (DG-6-P). As a direct consequence of tissue heterogeneity, the effective rate constant for phosphorylation of DG, k*3, declined with time. To compensate for the time-changing k*3, estimates of the dephosphorylation rate constant, k*4, were artifactually high when the 4K model was used, even though no dephosphorylation of DG-6-P actually occurred. The present study demonstrates that the finding of a significant k*4, at least within 45 min following a pulse of DG, may not represent dephosphorylation at all, but rather the consequence of measuring radioactivity in a heterogeneous tissue and applying a model designed for a homogeneous tissue. Furthermore, the high estimates of k*4 resulted in significant overestimation of rCMRglc. When rCMRglc was computed with the conventional single-scan or autoradiographic method at 45 min after a pulse of DG, the 3K and tissue heterogeneity models yielded values that were within 5% of the true weighted average value for the heterogeneous tissue as a whole. We conclude that the effects of tissue heterogeneity alone can give the appearance of product loss, even when none occurs, and that the use of the 4K model with the assumption of product loss in the 45-min experimental period recommended for the DG method may lead to overestimation of the rates of glucose utilization.

scholarly journals Kinetic and Microhydrodynamic Modeling of Fenofibrate Nanosuspension Production in a Wet Stirred Media Mill

Pharmaceutics ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1055
Author(s):  
Gulenay Guner ◽  
Dogacan Yilmaz ◽  
Ecevit Bilgili
Keyword(s):  
Rate Constant ◽  
Kinetic Models ◽  
Multiple Linear Regression Model ◽  
Empirical Correlation ◽  
P Value ◽  
Order Kinetic ◽  
Stirrer Speed ◽  
Predictive Capability ◽  
Breakage Rate ◽  
The Impact

This study examined the impact of stirrer speed and bead material loading on fenofibrate particle breakage during wet stirred media milling (WSMM) via three kinetic models and a microhydrodynamic model. Evolution of median particle size was tracked via laser diffraction during WSMM operating at 3000–4000 rpm with 35–50% (v/v) concentration of polystyrene or zirconia beads. Additional experiments were performed at the center points of the above conditions, as well as outside the range of these conditions, in order to test the predictive capability of the models. First-order, nth-order, and warped-time kinetic models were fitted to the data. Main effects plots helped to visualize the influence of the milling variables on the breakage kinetics and microhydrodynamic parameters. A subset selection algorithm was used along with a multiple linear regression model (MLRM) to delineate how the breakage rate constant k was affected by the microhydrodynamic parameters. As a comparison, a purely empirical correlation for k was also developed in terms of the process/bead parameters. The nth-order model was found to be the best model to describe the temporal evolution; nearly second-order kinetics (n ≅ 2) was observed. When the process was operated at a higher stirrer speed and/or higher loading with zirconia beads as opposed to polystyrene beads, the breakage occurred faster. A statistically significant (p-value ≤ 0.01) MLRM of three microhydrodynamic parameters explained the variation in the breakage rate constant best (R2 ≥ 0.99). Not only do the models and the nth-order kinetic–microhydrodynamic correlation enable deeper process understanding toward developing a WSMM process with reduced cycle time, but they also provide good predictive capability, while outperforming the purely empirical correlation.

scholarly journals On apparent barrier-free reactions

2020 ◽  
Vol 3 (1) ◽  
pp. 3-8
Author(s):  
Maikel Ballester
Keyword(s):  
Low Temperature ◽  
Chemical Reactions ◽  
Rate Constant ◽  
Kinetic Models ◽  
Rate Coefficient ◽  
Minimum Energy ◽  
Temperature Limit ◽  
Rate Coefficients ◽  
Minimum Energy Path ◽  
Full Dimension

Rate coefficients of bi-molecular chemical reactions are fundamental for kinetic models. The rate coefficient dependence on temperature is commonly extracted from the analyses of the reaction minimum energy path. However, a full dimension study of the same reaction may suggest a different asymptotic low-temperature limit in the rate constant than the obtained from the energetic profile.

Clinical Pharmacokinetics of Irinotecan and Its Metabolites: A Population Analysis

2002 ◽  
Vol 20 (15) ◽  
pp. 3293-3301 ◽  
Author(s):  
Rujia Xie ◽  
Ron H.J. Mathijssen ◽  
Alex Sparreboom ◽  
Jaap Verweij ◽  
Mats O. Karlsson
Keyword(s):  
Tissue Distribution ◽  
Goodness Of Fit ◽  
Population Analysis ◽  
Dose Range ◽  
Central Compartment ◽  
Volume Of Distribution ◽  
Population Pharmacokinetic ◽  
Clinical Pharmacokinetics ◽  
Lactone Form ◽  
Time Courses

PURPOSE: To build population pharmacokinetic (PK) models for irinotecan (CPT-11) and its currently identified metabolites. PATIENTS AND METHODS: Seventy cancer patients (24 women and 46 men) received 90-minute intravenous infusions of CPT-11 in the dose range of 175 to 300 mg/m2. The PK models were developed to describe plasma concentration profiles of the lactone and carboxylate forms of CPT-11 and 7-ethyl-10-hydroxycamptothecin (SN-38) and the total forms of SN-38 glucuronide (SN-38G), 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin (APC), and 7-ethyl-10-[4-amino-1-piperidino]-carbonyloxycamptothecin (NPC) by using NONMEM. RESULTS: The interconversion between the lactone and carboxylate forms of CPT-11 was relatively rapid, with an equilibration half-life of 14 minutes in the central compartment and hydrolysis occurring at a rate five times faster than lactonization. The same interconversion also occurred in peripheral compartments. CPT-11 lactone had extensive tissue distribution (steady-state volume of distribution [Vss], 445 L) compared with the carboxylate form (Vss, 78 L, excluding peripherally formed CPT-11 carboxylate). Clearance (CL) was higher for the lactone form (74.3 L/h) compared with the carboxylate form (12.3 L/h). During metabolite data modeling, goodness of fit indicated a preference of SN-38 and NPC to be formed out of the lactone form of CPT-11, whereas APC could be modeled best by presuming formation from CPT-11 carboxylate. The interconversion between SN-38 lactone and carboxylate was slower than that of CPT-11, with the lactone form dominating at equilibrium. The CLs for SN-38 lactone and carboxylate were similar, but the lactone form had more extensive tissue distribution. CONCLUSION: Plasma data of CPT-11 and metabolites could be adequately described by this compartmental model, which may be useful in predicting the time courses, including interindividual variability, of all characterized substances after intravenous administrations of CPT-11.

Multiple glucose 6-phosphate pools or channelling of flux in diverse pathways?

2002 ◽  
Vol 30 (2) ◽  
pp. 38-43 ◽  
Author(s):  
Loranne Agius ◽  
Josep Centelles ◽  
Marta Cascante
Keyword(s):  
Gene Expression ◽  
Enzyme Activity ◽  
Glucose Utilization ◽  
Cell Extract ◽  
Phosphate Content ◽  
Metabolic Intermediates ◽  
Expression Studies ◽  
Gene Expression Studies ◽  
Total Tissue ◽  
Whole Cell Extract

Glucose 6-phosphate is an intermediate of pathways of glucose utilization and production as well as a regulator of enzyme activity and gene expression. Studies on the latter functions are in part based on measurement of the glucose 6-phosphate content in a whole-cell extract. Several studies have suggested that there are multiple subcellular pools of glucose 6-phosphate. It is proposed that this data can be interpreted in terms of channelling of metabolic intermediates through multiple pathways of glucose metabolism with leakage of glucose 6-phosphate from the channels into a single free pool. It is also proposed that measurement of total tissue content of glucose 6-phosphate approximates the free pool.

scholarly journals Glutamatergic Neurotransmission and Neuronal Glucose Oxidation are Coupled during Intense Neuronal Activation

2004 ◽  
Vol 24 (9) ◽  
pp. 972-985 ◽  
Author(s):  
Anant B. Patel ◽  
Robin A. de Graaf ◽  
Graeme F. Mason ◽  
Tomoyuki Kanamatsu ◽  
Douglas L. Rothman ◽  
...  
Keyword(s):  
Glucose Oxidation ◽  
Glucose Utilization ◽  
Lactate Concentration ◽  
Sensory Stimulation ◽  
Tca Cycle ◽  
Cortical Activation ◽  
Positron Emission ◽  
Time Courses ◽  
Total Glucose ◽  
The Relationship

13C nuclear magnetic resonance (NMR) experiments have previously shown that glutamatergic neurotransmitter flux (Vcycle(Glu/Gln)) changes proportionately with neuronal glucose oxidation (CMRglc(ox)N) in the nonactivated cortex of anesthetized rats. Positron Emission Tomography measurements of glucose and oxygen uptake during sensory stimulation had shown that the incremental glucose utilization is greater than oxygen leading to the suggestion that the energy required for stimulated neuronal activity arises from nonoxidative glucose metabolism. In this study, the authors used spatially localized 1H-observed, 13C-edited NMR spectroscopy during an infusion of [1,6–13C2]glucose to assess the relationship between changes in Vcycle(Glu/Gln) and glucose utilization (CMRglc(ox)N and CMRglc(nonox)) during the intense cortical activity associated with bicuculline-induced seizures. Metabolic fluxes were determined by model-based analysis of the 13C-enrichment time courses of glutamate-C4 and glutamine-C4 (CMRglc(ox)N, Vcycle(Glu/Gln)) and lactate-C3 (CMRglc(nonox)). The exchange rate between α-ketoglutarate and glutamate was found to be significantly faster than TCA cycle flux both for control (41 μmol·g−1·min−1; 95% CI, 5 to 109 μmol·g−1·min−1) and during seizures (21 μmol·g−1·min−1; 95% CI, 4.4 to 51.8 μmol·g−1·min−1). During seizures, total glucose utilization (CMRglc(ox+nonox)) increased substantially (466% between 0 and 6 minutes; 277% between 6 and 55 minutes). Glucose oxidation (CMRglc(ox)N) also increased (214%; from 0.26 ± 0.02 to 0.57 ± 0.07 μmol·g−1·min−1) but to a lesser degree, resulting in a large increase in cortical lactate concentration. Vcycle(Glu/Gln) increased 233% (from 0.22 ± 0.04 to 0.52 ± 0.07 μmol·g−1·min−1), which was similar to the increase in glucose oxidation. The value of Vcycle(Glu/Gln) and CMRglc(ox)N obtained here lie on the line predicted in a previous study. These results indicate that neuronal glucose oxidation and not total glucose utilization is coupled to the glutamate/glutamine cycle during intense cortical activation.

Human RhAG ammonia channel is impaired by the Phe65Ser mutation in overhydrated stomatocytic red cells

2012 ◽  
Vol 302 (2) ◽  
pp. C419-C428 ◽  
Author(s):  
Sandrine Genetet ◽  
Pierre Ripoche ◽  
Julien Picot ◽  
Sylvain Bigot ◽  
Jean Delaunay ◽  
...  
Keyword(s):  
Intracellular Ph ◽  
Hemolytic Anemia ◽  
Rate Constant ◽  
Rate Constants ◽  
Flow Analysis ◽  
Red Cells ◽  
Stopped Flow ◽  
Loss Of Function ◽  
Dramatic Decrease ◽  
Time Courses

In red cells, Rh-associated glycoprotein (RhAG) acts as an ammonia channel, as demonstrated by stopped-flow analysis of ghost intracellular pH (pHi) changes. Recently, overhydrated hereditary stomatocytosis (OHSt), a rare dominantly inherited hemolytic anemia, was found to be associated with a mutation (Phe65Ser or Ile61Arg) in RHAG. Ghosts from the erythrocytes of four of the OHSt patients with a Phe65Ser mutation were resealed with a pH-sensitive probe and submitted to ammonium gradients. Alkalinization rate constants, reflecting NH3transport through the channel and NH3diffusion unmediated by RhAG, were deduced from time courses of fluorescence changes. After subtraction of the constant value found for Rhnulllacking RhAG, we observed that alkalinization rate constant values decreased ∼50% in OHSt compared with those of controls. Similar RhAG expression levels were found in control and OHSt. Since half of the expressed RhAG in OHSt most probably corresponds to the mutated form of RhAG, as expected from the OHSt heterozygous status, this dramatic decrease can be therefore related to the loss of function of the Phe65Ser-mutated RhAG monomer.

The Order of Kinetic Models, Rate Constant Distribution, and Maximum Combustible Recovery in Gilsonite Flotation

2019 ◽  
Vol 36 (6) ◽  
pp. 1101-1114
Author(s):  
Ataallah Bahrami ◽  
Fatemeh Kazemi ◽  
Yousef Ghorbani ◽  
Jafar Abdolahi Sharif
Keyword(s):  
Rate Constant ◽  
Kinetic Models ◽  
Rate Constant Distribution ◽  
Constant Distribution

scholarly journals Estimation of Local Cerebral Glucose Utilization by Positron Emission Tomography: Comparison of [18F]2-Fluoro-2-Deoxy-D-Glucose and [18F]2-Fluoro-2-Deoxy-D-Mannose in Patients with Focal Brain Lesions

1991 ◽  
Vol 11 (3) ◽  
pp. 485-491 ◽  
Author(s):  
K. Wienhard ◽  
G. Pawlik ◽  
B. Nebeling ◽  
J. Rudolf ◽  
G. Fink ◽  
...  
Keyword(s):  
Rate Constant ◽  
Glucose Utilization ◽  
Brain Lesions ◽  
Emission Tomography ◽  
Local Cerebral Glucose Utilization ◽  
Regional Variability ◽  
Positron Emission ◽  
Lumped Constant ◽  
Regional Basis ◽  
Phosphorylation Rate

A comparative PET study of [18F]2-fluoro-2-deoxy-D-glucose (FDG) and [18F]2-fluoro-2-deoxy-D-mannose (FDM) uptake was performed in 13 patients with focal brain lesions. Differences between FDG and FDM with respect to model rate constants, lumped constant, and estimated metabolic rate for glucose were determined on a regional basis. Across whole brain, the transport rate constant K*1 was almost unchanged, whereas k*2, describing the transport back from tissue to plasma, was 6% higher, and the phosphorylation rate constant k*3 was 9% lower for FDM compared to FDG. This implies a 20% lower lumped constant for FDM. No significant regional variability of this differential tracer behavior was observed in normal or in lesioned brain tissue. Thus, results from previous FDG studies, where the radiotracer was not 100% pure FDG but contained varying amounts of FDM, can easily be corrected by adjustment of the lumped constant employed in metabolic quantitation.

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