Absence of glutamine isotopic steady state: implications for the assessment of whole-body glutamine production rate

1998 ◽  
Vol 95 (3) ◽  
pp. 339-346 ◽  
Author(s):  
Bernadette A. C. VAN ACKER ◽  
Karel W. E. HULSEWÉ ◽  
Anton J. M. WAGENMAKERS ◽  
Nicolaas E. P. DEUTZ ◽  
Bernard K. VAN KREEL ◽  
...  
Keyword(s):  
Steady State ◽  
Abdominal Surgery ◽  
Whole Body ◽  
Infusion Time ◽  
Isotopic Enrichment ◽  
Gradual Reduction ◽  
Appearance Rate ◽  
Comparison Of The Results ◽  
Glutamine Production ◽  
Large Muscle

1.During infusion of [5-15N]glutamine in patients with gastrointestinal cancer we unexpectedly observed a gradual decrease in time of the appearance rate (Ra) of glutamine in plasma. Here we investigate whether the failure to achieve a plateau isotopic enrichment in plasma is, among other factors, due to incomplete equilibration of the glutamine tracer with the large intramuscular free glutamine pool. 2.Plasma and intramuscular glutamine enrichment were measured during 6–11 ;h infusions of L-[5-15N]glutamine and L-[1-13C]glutamine in post-absorptive patients admitted to hospital for elective abdominal surgery. L-[1-13C]Leucine and L-[ring-2H5]phenylalanine were infused to measure the proportion of glutamine appearing in plasma directly due to its release from protein. 3.The glutamine tracer entered muscle, but the rise in intramuscular glutamine enrichment was small, presumably as a result of the enormous size of the intramuscular glutamine pool and the limited speed of entry of glutamine into muscle. In each patient the intramuscular glutamine enrichment was lower than that in plasma (P < 0.001), and both increased with tracer infusion time (P < 0.001), indicating incomplete equilibration of the glutamine tracer. 4.A comparison of the results obtained by the two glutamine tracers indicated that recycling of the nitrogen label contributed to about 15% of the decrease in Ra. 5.There was a gradual reduction in the glutamine release from proteolysis, which contributed to 16–21% of the decline in Ra. 6.We conclude that slow equilibration of the glutamine tracer with the large muscle glutamine pool significantly contributes to the absence of isotopic steady state. Consequently, the appearance rate of glutamine in plasma measured during short tracer infusion periods (hours) considerably overestimates the whole-body glutamine flux.

Evaluation of the isotopic equilibration between lactate and pyruvate

1988 ◽  
Vol 254 (4) ◽  
pp. E532-E535 ◽  
Author(s):  
R. R. Wolfe ◽  
F. Jahoor ◽  
H. Miyoshi
Keyword(s):  
Steady State ◽  
Metabolic Flux ◽  
Isotopic Exchange ◽  
Whole Body ◽  
Isotopic Enrichment ◽  
Isotopic Tracer ◽  
Anesthetized Dogs ◽  
Isotopic Equilibration ◽  
Lactate And Pyruvate ◽  
Kinetics Of

When an isotopic tracer is infused for the purpose of determining the rate of turnover or oxidation of a substrate, it is assumed that the resulting isotopic enrichment by the tracer will reflect the kinetics of only the pool of interest. However, this may not be the case when carbon-labeled lactate is infused, since rapid isotopic exchange with the intracellular pyruvate and alanine pools could potentially occur. Therefore we have determined the extent of isotopic exchange occurring during the infusion of [3-13C]lactate into six anesthetized dogs. In the steady state, pyruvate enrichment was 91 +/- 2.2% (means +/- SE) of the lactate enrichment, and alanine enrichment was 81 +/- 3.3% of the pyruvate enrichment and 72 +/- 2.6% of the lactate enrichment. In contrast, when [3-13C]alanine was infused (n = 2), pyruvate (and lactate) enrichment was 9.9% of the alanine enrichment. We therefore conclude that there is rapid isotopic equilibration between lactate and pyruvate but that interaction with alanine reflects the true metabolic flux rates, rather than isotopic exchange. Consequently, lactate kinetics, as traditionally determined, more accurately reflect whole body pyruvate kinetics.

Absence of glutamine isotopic steady state: implications for the assessment of whole-body glutamine production rate

1998 ◽  
Vol 95 (3) ◽  
pp. 339 ◽  
Author(s):  
Bernadette A.C. VAN ACKER ◽  
Karel W.E. HULSEWÉ ◽  
Anton J.M. WAGENMAKERS ◽  
Nicolaas E.P. DEUTZ ◽  
Bernard K. VAN KREEL ◽  
...  
Keyword(s):  
Steady State ◽  
Production Rate ◽  
Whole Body ◽  
Glutamine Production

Whole Body Nitrogen Kinetics in Man: Determination from Plasma [Guanidino-15N]Arginine

1984 ◽  
Vol 66 (3) ◽  
pp. 337-342 ◽  
Author(s):  
Marc Yudkoff ◽  
Itzhak Nissim ◽  
Mark Glassman ◽  
Stanton Segal
Keyword(s):  
Protein Synthesis ◽  
Steady State ◽  
Molecular Medicine ◽  
Whole Body ◽  
Constant Infusion ◽  
Isotopic Enrichment ◽  
Healthy Young Adult ◽  
Metabolic Pool ◽  
15N Urea ◽  
Oral Doses

1. Whole body nitrogen turnover and protein synthesis were calculated by the method of D. Picou & T. Taylor-Roberts [Clinical Science and Molecular Medicine (1969) 36, 283–296] except that plateau plasma enrichment of [guanidino-15N]arginine was used in place of the [15N]urea enrichment after a constant infusion of [15N]-glycine. With this approach metabolic pool turnover and protein synthesis were 637.2 ± 73.0 mg of N day−1 kg−1 and 2964.0 ± 409.5 mg of protein day−1 kg−1 respectively. 2. Virtually identical isotopic enrichment in [guanidino-15N]arginine and [15N]urea were observed in a healthy young adult who took repeated oral doses of [15N]glycine for a period of 60 h: 0.47 (arginine) and 0.48 (urea) atom% excess. 3. The turnover of glycine nitrogen and of urea, determined from the constant infusion of [15N]glycine and [13C]urea, was 66.2 ± 3.3 mg of N day−1 kg−1 and 156.2 ± 4.3 mg of urea day−1 kg−1 respectively. The ratio of steady-state enrichment in arginine to that in glycine, reflecting the fraction of arginine derived from glycine, was 10.5%. By using the [guanidino-15N]arginine enrichment as representative of the expected enrichment in [15N]urea at plateau, it was calculated that approximately 25% of glycine N flux is directed toward the synthesis of urea, with the remainder directed to protein and quantitatively minor products like haem and creatinine. 4. Unlike steady-state [15N]urea labelling, which is achieved only after infusion of [15N]-glycine for several days, plateau isotopic abundance in [guanidino-15N]arginine was attained after only 1–2 h of [15N]glycine infusions, thereby allowing estimation of whole body nitrogen kinetics and the rate of transfer of glycine nitrogen to urea in a relatively brief experiment.

Continuous Estimation of CO2 Production during Exercise

1997 ◽  
Vol 36 (04/05) ◽  
pp. 368-371
Author(s):  
R. Soma ◽  
Y. Yamamoto
Keyword(s):  
Fuzzy Logic ◽  
Steady State ◽  
Infusion Rate ◽  
Feedback System ◽  
Whole Body ◽  
Co2 Production ◽  
Cycle Exercise ◽  
Continuous Estimation ◽  
Breath Measurement ◽  
13Co2 Enrichment

Abstract.A new method was developed for continuous isotopic estimation of human whole body CO2 rate of appearance (Ra) during non-steady state exercise. The technique consisted of a breath-by-breath measurement of 13CO2 enrichment (E) and a real-time fuzzy logic feedback system which controlled NaH13CO3 infusion rate to achieve an isotopic steady state. Ra was estimated from the isotope infusion rate and body 13CO2 enrichment which was equal to E at the isotopic steady state. During a non-steady state incremental cycle exercise (5 w/min or 10 w/min), NaH13CO3 infusion rate was successfully increased by the action of feedback controller so as to keep E constant.

Cyclic Breathing Simulations in Large Scale Models of the Lung Airway From the Oronasal Opening to the Terminal Bronchioles

2012 ◽  
Author(s):  
D. Keith Walters ◽  
Greg W. Burgreen ◽  
Robert L. Hester ◽  
David S. Thompson ◽  
David M. Lavallee ◽  
...  
Keyword(s):  
Steady State ◽  
Boundary Conditions ◽  
Large Scale ◽  
Whole Body ◽  
Patient Specific ◽  
Cfd Simulations ◽  
Reduced Order ◽  
Scale Models ◽  
Steady State Simulation ◽  
Conducting Zone

Computational fluid dynamics (CFD) simulations were performed for unsteady periodic breathing conditions, using large-scale models of the human lung airway. The computational domain included fully coupled representations of the orotracheal region and large conducting zone up to generation four (G4) obtained from patient-specific CT data, and the small conducting zone (to G16) obtained from a stochastically generated airway tree with statistically realistic geometrical characteristics. A reduced-order geometry was used, in which several airway branches in each generation were truncated, and only select flow paths were retained to G16. The inlet and outlet flow boundaries corresponded to the oronasal opening (superior), the inlet/outlet planes in terminal bronchioles (distal), and the unresolved airway boundaries arising from the truncation procedure (intermediate). The cyclic flow was specified according to the predicted ventilation patterns for a healthy adult male at three different activity levels, supplied by the whole-body modeling software HumMod. The CFD simulations were performed using Ansys FLUENT. The mass flow distribution at the distal boundaries was prescribed using a previously documented methodology, in which the percentage of the total flow for each boundary was first determined from a steady-state simulation with an applied flow rate equal to the average during the inhalation phase of the breathing cycle. The distal pressure boundary conditions for the steady-state simulation were set using a stochastic coupling procedure to ensure physiologically realistic flow conditions. The results show that: 1) physiologically realistic flow is obtained in the model, in terms of cyclic mass conservation and approximately uniform pressure distribution in the distal airways; 2) the predicted alveolar pressure is in good agreement with previously documented values; and 3) the use of reduced-order geometry modeling allows accurate and efficient simulation of large-scale breathing lung flow, provided care is taken to use a physiologically realistic geometry and to properly address the unsteady boundary conditions.

Tissue carbon dioxide stores: magnitude of acute change in the dog

1964 ◽  
Vol 206 (4) ◽  
pp. 887-890 ◽  
Author(s):  
S. F. Sullivan ◽  
R. W. Patterson ◽  
E. M. Papper
Keyword(s):  
Carbon Dioxide ◽  
Steady State ◽  
Dissociation Constant ◽  
Average Rate ◽  
Carbon Dioxide Tension ◽  
Whole Body ◽  
Limiting Factor ◽  
Acute Change ◽  
Washout Curves ◽  
Mixed Venous

Carbon dioxide washout curves were determined in hyperventilated dogs. Direct measurement of mixed venous carbon dioxide tension allowed calculation of changes in whole-body CO2 stores. The average whole-body CO2 dissociation constant in ten studies was 3.73 ml/kg mm. The limiting factor in reaching a new steady-state value was represented by a slow compartment in the washout curve. The average rate constant for this compartment was 0.062 min–1. The slowest compartment in this analysis has a 98% change in 1 hr, therefore the experimentally determined whole-body dissociation constant should closely approximate actual changes in tissue CO2 stores, excluding bone and fat.

Availability of intestinal microbial lysine for whole body lysine homeostasis in human subjects

1999 ◽  
Vol 277 (4) ◽  
pp. E597-E607 ◽  
Author(s):  
Cornelia C. Metges ◽  
Antoine E. El-Khoury ◽  
Lidewij Henneman ◽  
Klaus J. Petzke ◽  
Ian Grant ◽  
...  
Keyword(s):  
De Novo ◽  
Human Subjects ◽  
Isotope Ratio Mass Spectrometry ◽  
Acid Synthesis ◽  
Whole Body ◽  
Microbial Protein ◽  
Amino Acid Synthesis ◽  
Adequate Diet ◽  
Appearance Rate ◽  
Intravenous And Oral Administration

We have investigated whether there is a net contribution of lysine synthesized de novo by the gastrointestinal microflora to lysine homeostasis in six adults. On two separate occasions an adequate diet was given for a total of 11 days, and a 24-h (12-h fast, 12-h fed) tracer protocol was performed on the last day, in which lysine turnover, oxidation, and splanchnic uptake were measured on the basis of intravenous and oral administration ofl-[1-13C]lysine andl-[6,6-2H2]lysine, respectively. [15N2]urea or15NH4Cl was ingested daily over the last 6 days to label microbial protein. In addition, seven ileostomates were studied with15NH4Cl. [15N]lysine enrichment in fecal and ileal microbial protein, as precursor for microbial lysine absorption, and in plasma free lysine was measured by gas chromatography-combustion-isotope ratio mass spectrometry. Differences in plasma [13C]- and [2H2]lysine enrichments during the 12-h fed period were observed between the two15N tracer studies, although the reason is unclear, and possibly unrelated to the tracer form per se. In the normal adults, after15NH4Cl and [15N2]urea intake, respectively, lysine derived from fecal microbial protein accounted for 5 and 9% of the appearance rate of plasma lysine. With ileal microbial lysine enrichment, the contribution of microbial lysine to plasma lysine appearance was 44%. This amounts to a gross microbial lysine contribution to whole body plasma lysine turnover of between 11 and 130 mg ⋅ kg−1 ⋅ day−1, depending on the [15N]lysine precursor used. However, insofar as microbial amino acid synthesis is accompanied by microbial breakdown of endogenous amino acids or their oxidation by intestinal tissues, this may not reflect a net increase in lysine absorption. Thus we cannot reliably estimate the quantitative contribution of microbial lysine to host lysine homeostasis with the present paradigm. However, the results confirm the significant presence of lysine of microbial origin in the plasma free lysine pool.

scholarly journals 1396. Predictions of Isavuconazonium Sulfate Dosage in Patients Aged 6 Months: <18 Years by Physiologically Based Pharmacokinetic Modeling

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S429-S430 ◽  
Author(s):  
Amit Desai ◽  
Laura Kovanda ◽  
Christopher Lademacher ◽  
William Hope ◽  
Michael Neely ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Steady State ◽  
Allometric Scaling ◽  
Pbpk Model ◽  
Whole Body ◽  
Target Range ◽  
Independent Contractor ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based ◽  
Research Grant

Abstract Background Best practice to establish dosage regimens for “first-in-pediatric” clinical trials requires knowledge of efficacious and safe exposures in adults. Methods Pediatric equivalent doses were predicted for patients aged 6 months and &lt;18 years using physiologically based pharmacokinetic (PBPK) modeling, and compared with predictions by allometric scaling. All simulations were completed using PK-Sim®, which implements a whole-body PBPK model with 15 organs and appropriate maturation of anatomical and physiological parameters for children. The adult PBPK model was built using knowledge of drug physico-chemistry and clearance partitioning (CYP3A4, CYP3A5, glomerular filtration). PK data following IV (40, 80, 160 mg 60-minute infusion) and oral (100, 200, 400 mg capsule) doses in adults were used for initial model development. This model was validated by matching observed adult concentrations after multiple oral 200 mg doses. From this adult model, a virtual pediatric population (n = 4,600) from 6 months to &lt;18 years was created. Simulations with the pediatric model assessed optimal doses of isavuconazonium sulfate based on age and weight to achieve at least a median steady-state daily area under the curve (AUCss) of 100 mg hour/L, and the majority below 230 mg hour/L. These targets were derived from efficacy and safety data in clinical trials with adults. Results As shown in the figure, an isavuconazonium sulfate dose of 10 mg/kg is expected to result in AUCss within the target range for the majority of patients &gt;1 year old, in agreement with that predicted by allometry for patients aged 2–17 years. For patients aged 6 months to 1 year, a dose of 6 mg/kg predicts comparable exposures. Conclusion A proposed isavuconazonium sulfate dose of 10 mg/kg administered every 8 hours for the first 2 days and once daily thereafter is predicted to result in safe and efficacious steady state exposures in patients aged 1–17 years, similar to predictions from allometric scaling for patients aged 2–17 years. For subjects aged 6 months to 1 year, a dose of 6 mg/kg is predicted to achieve similar exposures. These doses should be tested in clinical trials to confirm. Disclosures A. Desai, Astellas Pharma, Inc.: Employee, Salary. L. Kovanda, Astellas Pharma, Inc.: Employee, Salary. C. Lademacher, Astellas Pharma, Inc.: Employee, Salary. W. Hope, F2G: Grant Investigator and Scientific Advisor, Consulting fee and Research grant. Astellas: Grant Investigator and Investigator, Grant recipient and Research grant. Pfizer: Grant Investigator, Research support. Gilead: Consultant and Scientific Advisor, Consulting fee. P. Bonate, Astellas Pharma, Inc.: Employee, Salary. A. Edginton, Astellas Pharma Global Development, Inc.: Independent Contractor, Consulting fee.

Physiological effects of endogenous ouabain: control of intracellular Ca2+ stores and cell responsiveness

1993 ◽  
Vol 264 (6) ◽  
pp. C1367-C1387 ◽  
Author(s):  
M. P. Blaustein
Keyword(s):  
Steady State ◽  
Cell Types ◽  
Whole Body ◽  
Cellular Mechanisms ◽  
Signaling Mechanism ◽  
Physiological Processes ◽  
Endogenous Ouabain ◽  
Adrenal Cortical Hormone ◽  
Salt And Water Balance

Ouabain is a well-known compound but a newly discovered adrenal cortical hormone that plays a role in cell Na+ regulation and in whole body salt and water balance. Ouabain may also be a paracrine hormone and may be secreted by some central nervous system neurons as well as by other types of cells. This article focuses on the cellular mechanisms that underlie the physiological (and pathophysiological) effects of ouabain. Ouabain directly inhibits the plasmalemmal Na+ pump in a variety of cell types. Low ouabain concentrations cause, in the steady state, a modest rise in the cytosolic Na+ concentration but only a minimal decline in membrane potential. All Na+ gradient-dependent processes may thereby be affected, albeit to only a small extent. Most important, however, is the secondary redistribution of Ca2+, mediated by Na(+)-Ca2+ exchange, that should slightly increase the cytosolic free Ca2+ concentration ([Ca2+]cyt). As a result of Ca2+ sequestration in intracellular stores [the endoplasmic and/or sarcoplasmic reticulum (ER/SR)], however, a new steady state is achieved with a slightly increased [Ca2+]cyt but a substantially augmented Ca2+ store; thus the ER/SR effectively acts as a Ca2+ amplifier. This extra stored Ca2+ is then available for mobilization whenever the cells are activated. Cytosolic Ca2+ is a key signaling mechanism in virtually all cells: it controls numerous physiological processes such as contraction, secretion, and excitability. Thus ouabain may modulate cell responsiveness via its influence on ER/SR Ca2+ stores. With these principles in mind, we examine evidence that endogenous ouabain may play a role in numerous physiological and pathophysiological processes associated with altered fluid and electrolyte metabolism and deviations from the normal blood pressure-blood volume relationship. We discuss the possible participation of ouabain in the regulation of vascular tone and then consider the putative role of ouabain in several forms of hypertension, congestive heart failure, thyroid and adrenocortical dysfunction, and diabetes mellitus, as well as in the adaptation to high altitude.

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