Tracer Concentration In Plasma Research Articles

Exact parameter identification in PET pharmacokinetic modeling using the irreversible two tissue compartment model.

In quantitative dynamic positron emission tomography (PET), time series of images, reflecting the tissue response to the arterial tracer supply, are reconstructed. This response is described by kinetic parameters, which are commonly determined on basis of the tracer concentration in tissue and the arterial input function. In clinical routine the latter is estimated by arterial blood sampling and analysis, which is a challenging process and thus, attempted to be derived directly from reconstructed PET images. However, a mathematical analysis about the necessity of measurements of the common arterial whole blood activity concentration, and the concentration of free non-metabolized tracer in the arterial plasma, for a successful kinetic parameter identification does not exist. Here we aim to address this problem mathematically. 
Approach: We consider the identification problem in simultaneous pharmacokinetic modeling of multiple regions of interests of dynamic PET data using the irreversible two-tissue compartment model analytically. In addition to this consideration, the situation of noisy measurements is addressed using Tikhonov regularization. Furthermore, numerical simulations with a regularization approach are carried out to illustrate the analytical results in a synthetic application example.
Main results: We provide mathematical proofs showing that, under reasonable assumptions, all metabolic tissue parameters can be uniquely identified without requiring additional blood samples to measure the arterial input function. A connection to noisy measurement data is made via a consistency result, showing that exact reconstruction of the ground-truth tissue parameters is stably maintained in the vanishing noise limit. Furthermore, our numerical experiments suggest that an approximate reconstruction of kinetic parameters according to our analytic results is also possible in practice for moderate noise levels.
Significance: The analytical result, which holds in the idealized, noiseless scenario, suggests that for irreversible tracers, fully quantitative dynamic PET imaging is in principle possible without costly arterial blood sampling and metabolite analysis.

Development of simultaneous determination of dopamine 2, histamine 1, and muscarinic acetylcholine receptor occupancies by antipsychotics using liquid chromatography with tandem mass spectrometry

Receptor occupancy is an indicator of antipsychotic efficacy and safety. It is desirable to simultaneously determine the occupancy of multiple brain receptors as an indicator of the efficacy and central side effects of antipsychotics because many of these drugs have binding affinities for various receptors, such as dopamine 2 (D2), histamine 1 (H1), and muscarinic acetylcholine (mACh) receptors. The purpose of this study was to develop a method for the simultaneous measurement of multiple receptor occupancies in the brain by the simultaneous quantification of unlabeled tracer levels using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Rats were pre-administered with a vehicle, displacer, or olanzapine, and mixed solutions of raclopride, doxepin, and 3-quinuclidinyl benzilate (3-QNB) were administered (3, 10, and 30 μg/kg). The brain tissue and plasma tracer concentrations were quantified 45 min later using LC-MS/MS, and the binding potential was calculated. The highest binding potential was observed at 3 μg/kg raclopride, 10 μg/kg doxepin, and 30 μg/kg 3-QNB. Tracer-specific binding at these optimal tracer doses in the cerebral cortex was markedly reduced by pre-administration of displacers. D2, H1, and mACh receptor occupancy by olanzapine increased in a dose-dependent manner, reaching 70–95%, 19–43%, and 12–45%, respectively, at an olanzapine dose range of 3–10 mg/kg. These results suggest that simultaneous determination of in vivo D2, H1, and mACh receptor occupancy is possible using LC-MS/MS.

Patient-Adaptive Population-Based Modeling of Arterial Input Functions.

Kinetic modeling of dynamic PET data requires knowledge of tracer concentration in blood plasma, described by the arterial input function (AIF). Arterial blood sampling is the gold standard for AIF measurement, but is invasive and labour intensive. A number of methods have been proposed to accurately estimate the AIF directly from blood sampling and/or imaging data. Here we consider fitting a patient-adaptive mixture of historical population time course profiles to estimate individual AIFs. Travel time of a tracer atom from the injection site to the right ventricle of the heart is modeled as a realization from a Gamma distribution, and the time this atom spends in circulation before being sampled is represented by a subject-specific linear mixture of population profiles. These functions are estimated from independent population data. Individual AIFs are obtained by projection onto this basis of population profile components. The model incorporates knowledge of injection duration into the fit, allowing for varying injection protocols. Analyses of arterial sampling data from 18F-FDG, 15O-H2O and 18F-FLT clinical studies show that the proposed model can outperform reference techniques. The statistically significant gain achieved by using population data to train the basis components, instead of fitting these from the single individual sampling data, is measured on the FDG cohort. Kinetic analyses of simulated data demonstrate the reliability and potential benefit of this approach in estimating physiological parameters. These results are further supported by numerical simulations that demonstrate convergence and stability of the proposed technique under varying training population sizes and noise levels.

Modeling venous plasma samples in [18F] FDG PET studies: a nonlinear mixed-effects approach.

The gold-standard approach to quantifying dynamic PET images relies on using invasive measures of the arterial plasma tracer concentration. An attractive alternative is to employ an image-derived input function (IDIF), corrected for spillover effects and rescaled with venous plasma samples. However, venous samples are not always available for every participant. In this work, we used the nonlinear mixed-effects modeling approach to develop a model which infers venous tracer kinetics by using venous samples obtained from a population of healthy individuals and integrating subject-specific covariates. Population parameters (fixed effects), their between-subject variability (random effects), and the effects of covariates were estimated. The selected model will allow to reliably infer venous tracer kinetics in subjects with missing measurements. Clinical relevance - The derived model will be relevant for fully noninvasive dynamic FDG PET quantification using image-derived input functions in both healthy and patient populations when hemodynamics is not impaired.

In vivo quantitative mapping of human mitochondrial cardiac membrane potential: a feasibility study.

Alteration in mitochondrial membrane potential (ΔΨm) is an important feature of many pathologic processes, including heart failure, cardiotoxicity, ventricular arrhythmia, and myocardial hypertrophy. We present the first in vivo, non-invasive, assessment of regional ΔΨm in the myocardium of normal human subjects. Thirteen healthy subjects were imaged using [18F]-triphenylphosphonium ([18F]TPP+) on a PET/MR scanner. The imaging protocol consisted of a bolus injection of 300MBq followed by a 120-min infusion of 0.6MBq/min. A 60min, dynamic PET acquisition was started 1h after bolus injection. The extracellular space fraction (fECS) was simultaneously measured using MR T1-mapping images acquired at baseline and 15min after gadolinium injection with correction for the subject's hematocrit level. Serial venous blood samples were obtained to calculate the plasma tracer concentration. The tissue membrane potential (ΔΨT), a proxy of ΔΨm, was calculated from the myocardial tracer concentration at secular equilibrium, blood concentration, and fECS measurements using a model based on the Nernst equation. In 13 healthy subjects, average tissue membrane potential (ΔΨT), representing the sum of cellular membrane potential (ΔΨc) and ΔΨm, was - 160.7 ± 3.7mV, in excellent agreement with previous in vitro assessment. In vivo quantification of the mitochondrial function has the potential to provide new diagnostic and prognostic information for several cardiac diseases as well as allowing therapy monitoring. This feasibility study lays the foundation for further investigations to assess these potential roles. Clinical trial identifier: NCT03265431.

Measurement, model prediction and uncertainty quantification of plasma clearance of cerium citrate in humans

Double tracer studies in healthy human volunteers with stable isotopes of cerium citrate were performed with the aim of investigating the gastro-intestinal absorption of cerium (Ce), its plasma clearance and urinary excretion. In the present work, results of the clearance of Ce in blood plasma are shown after simultaneous intravenous and oral administration of a Ce tracer. Inductively coupled plasma mass spectrometry was used to determine the tracer concentrations in plasma. The results show that about 80% of the injected Ce citrate cleared from the plasma within the 5mins post-administration. The data obtained are compared to a revised biokinetic model of Ce, which was initially developed by the International Commission on Radiological Protection (ICRP). The measured plasma clearance of Ce citrate was mostly consistent with that predicted by the ICRP biokinetic model. Furthermore, in an effort to quantify the uncertainty of the model prediction, the laboratory animal data on which the ICRP biokinetic Ce model is based, was analyzed. The measured plasma clearance and its uncertainty was also compared to the plasma clearance uncertainty predicted by the model. It was found that the measured plasma clearance during the first 15min after administration is in a good agreement with the modelled plasma clearance. In general, the measured clearance falls inside the 95% confidence interval predicted by the biokinetic model.

Vitamin E absorption and kinetics in healthy women, as modulated by food and by fat, studied using 2 deuterium-labeled α-tocopherols in a 3-phase crossover design

Determining the human vitamin E [α-tocopherol (α-T)] requirement is difficult, and novel approaches to assess α-T absorption and trafficking are needed. We hypothesized that the dual-isotope technique, using 2 deuterium-labeled [intravenous (IV) d6- and oral d3-] α-T, would be effective in determining α-T fractional absorption. Further, defined liquid meal (DLM) fat or fasting would modulate α-T fractional absorption and lipoprotein transport. A 3-phase cr ossover design was used. At 0 h, participants received IV d6-α-T and consumed d3-α-T with a 600-kcal DLM (40% or 0% fat) followed by controlled meals or by the 0% fat DLM, a 12-h fast, and then controlled meals. Blood samples and fecal samples were collected at intervals and analyzed by LC-MS. Pharmacokinetic parameters were calculated from plasma tracer concentrations and enrichments. Fractional absorption was calculated from d3- to d6-α-T areas under the curve, from a novel mathematical model, and from the balance method (oral d3-α-T minus fecal d3-α-T excreted). Estimated α-T fractional absorption during the 40% fat intervention was 55%±3% (mean±SEM; n=10), which was 9% less than during the 0% fat intervention (64%±3%, n=10; P<0.02). Fasting had no apparent effect (56%±3%, n=7), except it slowed plasma oral d3-α-T appearance. Both balance data and model outcomes confirmed that the DLM fat did not potentiate d3-α-T absorption. During the IV emulsion clearance, HDL rapidly acquired d6-α-T (21±2 nmol/L plasma per minute). During the first 8 h postdosing, triglyceride-rich lipoproteins (TRLs) were preferentially d3-α-T enriched relative to LDL or HDL, showing the TRL precursor role. Quantitatively, α-T absorption is not limited by fat absence or by fasting. However, α-T leaves the intestine by a process that is prolonged during fasting and potentiated by eating, suggesting that α-T absorption is highly dependent on chylomicron assembly processes. This trial was registered at clinicaltrials.gov as NCT00862433.

Comparison of analytical methods of brain [18F]FDG-PET after severe traumatic brain injury

BackgroundLoss of consciousness has been shown to reduce cerebral metabolic rates of glucose (CMRglc) measured by brain [18F]FDG-PET. Measurements of regional metabolic patterns by normalization to global cerebral metabolism or cerebellum may underestimate widespread reductions. New methodThe aim of this study was to compare quantification methods of whole brain glucose metabolism, including whole brain [18F]FDG uptake normalized to uptake in cerebellum, normalized to injected activity, normalized to plasma tracer concentration, and two methods for estimating CMRglc. Six patients suffering from severe traumatic brain injury (TBI) and ten healthy controls (HC) underwent a 10min static [18F]FDG-PET scan and venous blood sampling. ResultsExcept from normalizing to cerebellum, all quantification methods found significant lower level of whole brain glucose metabolism of 25–33% in TBI patients compared to HC. In accordance these measurements correlated to level of consciousness. Comparison with existing methodsOur study demonstrates that the analysis method of the [18F]FDG PET data has a substantial impact on the estimated whole brain cerebral glucose metabolism in patients with severe TBI. Importantly, the SUVR method which is often used in a clinical setting was not able to distinguish patients with severe TBI from HC at the whole-brain level. ConclusionWe recommend supplementing a static [18F]FDG scan with a single venous blood sample in future studies of patients with severe TBI or reduced level of consciousness. This can be used for simple semi-quantitative uptake values by normalizing brain activity uptake to plasma tracer concentration, or quantitative estimates of CMRglc.

First-in-Human Assessment of the Novel PDE2A PET Radiotracer 18F-PF-05270430.

This was a first-in-human study of the novel phosphodiesterase-2A (PDE2A) PET ligand (18)F-PF-05270430. The primary goals were to determine the appropriate tracer kinetic model to quantify brain uptake and to examine the within-subject test-retest variability. In advance of human studies, radiation dosimetry was determined in nonhuman primates. Six healthy male subjects participated in a test-retest protocol with dynamic scans and metabolite-corrected input functions. Nine brain regions of interest were studied, including the striatum, white matter, neocortical regions, and cerebellum. Multiple modeling methods were applied to calculate volume of distribution (VT) and binding potentials relative to the nondisplaceable tracer in tissue (BPND), concentration of tracer in plasma (BPP), and free tracer in tissue (BPF). The cerebellum was selected as a reference region to calculate binding potentials. The dosimetry study provided an effective dose of less than 0.30 mSv/MBq, with the gallbladder as the critical organ; the human target dose was 185 MBq. There were no adverse events or clinically detectable pharmacologic effects reported. Tracer uptake was highest in the striatum, followed by neocortical regions and white matter, and lowest in the cerebellum. Regional time-activity curves were well fit by multilinear analysis-1, and a 70-min scan duration was sufficient to quantify VT and the binding potentials. BPND, with mean values ranging from 0.3 to 0.8, showed the best intrasubject and intersubject variability and reliability. Test-retest variability in the whole brain (excluding the cerebellum) of VT, BPND, and BPP were 8%, 16%, and 17%, respectively. (18)F-PF-05270430 shows promise as a PDE2A PET ligand, albeit with low binding potential values.

Modelling arterial input functions in positron emission tomography dynamic studies.

The quantification of dynamic positron emission tomography (PET) images often requires the invasive measures of the arterial plasma tracer concentration to be used as arterial input function (AIF). In several situations, a mathematical model is fit to the hematic data to obtain a continuous and noise-free description of the AIF. In common practice, the tri-exponential and Feng's models are generally adopted. Despite their general applicability, often these approximations of blood tracer activity do not properly describe the complex behavior of the AIF (e.g. different clearance rates of the tracers) as well as they do not account for the length of the radiotracer injection. Here we propose two models able to include the injection duration as additional information in the AIF modeling and we compare their performances in eight different datasets acquired from different PET facilities.

Combining MRI with PET for partial volume correction improves image-derived input functions in mice.

Accurate kinetic modelling using dynamic PET requires knowledge of the tracer concentration in plasma, known as the arterial input function (AIF). AIFs are usually determined by invasive blood sampling, but this is prohibitive in murine studies due to low total blood volumes. As a result of the low spatial resolution of PET, image-derived input functions (IDIFs) must be extracted from left ventricular blood pool (LVBP) ROIs of the mouse heart. This is challenging because of partial volume and spillover effects between the LVBP and myocardium, contaminating IDIFs with tissue signal. We have applied the geometric transfer matrix (GTM) method of partial volume correction (PVC) to 12 mice injected with 18F-FDG affected by a Myocardial Infarction (MI), of which 6 were treated with a drug which reduced infarction size [1]. We utilised high resolution MRI to assist in segmenting mouse hearts into 5 classes: LVBP, infarcted myocardium, healthy myocardium, lungs/body and background. The signal contribution from these 5 classes was convolved with the point spread function (PSF) of the Cambridge split magnet PET scanner and a non-linear fit was performed on the 5 measured signal components. The corrected IDIF was taken as the fitted LVBP component. It was found that the GTM PVC method could recover an IDIF with less contamination from spillover than an IDIF extracted from PET data alone. More realistic values of Ki were achieved using GTM IDIFs, which were shown to be significantly different (p<0.05) between the treated and untreated groups.

Quantification of the glycine transporter 1 in rhesus monkey brain using [18F]MK-6577 and a model-based input function

Glycine transporter 1 (GlyT1) inhibitors have emerged as potential treatments for schizophrenia due to their potentiation of NMDA receptor activity by modulating the local concentrations of the NMDA co-agonist glycine. [18F]MK-6577 is a potent and selective GlyT1 inhibitor PET tracer. Although differences in ligand kinetics can be expected between non-human primates and humans, the tracer pre-clinical evaluation can provide valuable information supporting protocol design and quantification in the clinical space. The main objective of this work was to evaluate the in vivo kinetics of [18F]MK-6577 in rhesus monkey brain. Additionally, a method for estimating the tracer input function from the tracer brain tissue kinetics and venous sampling was validated. This technique was applied for determination of the dose-occupancy relationship of a GlyT1 inhibitor in monkey brain. Compartmental and Logan graphical analysis were utilized for quantification of the [18F]MK-6577 binding using the measured tracer arterial input function. The stability of the tracer volume of distribution relative to scan length was assessed. The proposed model-based input function method takes advantage of the agreement between the tracer concentration in arterial and venous plasma from ~5 min. The approach estimates the initial peak of the input curve by adding a gamma like function term to the measured venous curve. The parameters of the model function were estimated by simultaneously fitting several brain time activity curves to a compartmental model. Good agreement was found between the model-based and the measured arterial plasma curve and the corresponding distribution volumes. The Logan analysis was the preferred method of analysis providing reliable and stable volume of distribution and occupancy results using a 90 and possibly 60 min scan length. The model-based input function method and Logan analysis are well suited for quantification of [18F]MK-6577 binding and GlyT1 occupancy in monkey brain.

Plasma clearance and urinary excretion after intravenous injection of stable 84Sr in humans

Systemic kinetics and urinary excretion after intravenous injection of stable strontium 84Sr were evaluated in 42 investigations in human subjects. Tracer concentrations in plasma and urine were determined by thermal ionisation mass spectrometry. The initial strontium plasma clearance measured after tracer administration was found to be much faster than that predicted by the current model of the International Commission of Radiological Protection (ICRP). The biological half-life of the fast component plasma clearance (T(1/2)) was 0.25 h in comparison with 1.1 h of the ICRP value. This early clearance could be the consequence of a more rapid transfer from blood plasma to other compartments of the human body. In vitro blood tests have shown that strontium was not bound to red blood cells. Cumulative urinary excretion is considerably lower than the model prediction. The reason could be the reduced transfer rate of strontium from plasma to urine in the first 12 h after tracer administration. Plasma clearance and urinary excretion showed no dependency on the age or gender of the adult volunteers.

Vitamin A kinetics and utilization in Chinese vs US adults

Vitamin A (VA) kinetics, storage, and utilization were compared in well-nourished Chinese (Wang Z et al., Br J Nutr; 91:–31, 2004) and US adults (Tang G et al., Am J Clin Nutr; 78:–66, 2003). [2H8]Retinyl acetate was orally administered (Chinese: n=15; 55 ± 4 y; mean ± SD and US: n=13; 60 ± 8 y), and plasma tracer and VA concentrations were measured from 3 h to 56 d. Data for plasma tracer vs time were fit to a 7-compartment model using the Simulation, Analysis and Modeling software (WinSAAM). The average time for the appearance of labeled retinol bound to retinol-binding protein in plasma was similar in both groups (~31 h). The plasma retinol pool was 3.34 ± 1.08 in Chinese vs 5.09 ± 1.11 μmol in US subjects (P<0.001); the model-predicted total VA pool was 232 ± 116 and 1866 ± 1603 μmol (P<0.002), and disposal rate was 4.74 ± 2.55 and 9.89 ± 5.15 μmol/d (P<0.0025). Based on these kinetic parameters, Chinese had 54.0 ± 26.9 d of VA stores vs 267 ± 314 d in US adults (P<0.016). Our results indicate that VA stores and disposal rates differ in healthy, well-nourished Chinese and US adults. (Chinese National Natural Science Foundation #30271121 and USDA #51000-065)

Assessment of input function distortions on kinetic model parameters in simulated dynamic 82Rb PET perfusion studies

Cardiac 82rubidium dynamic PET studies allow quantifying absolute myocardial perfusion by using tracer kinetic modeling. Here, the accurate measurement of the input function, i.e. the tracer concentration in blood plasma, is a major challenge. This measurement is deteriorated by inappropriate temporal sampling, spillover, etc. Such effects may influence the measured input peak value and the measured blood pool clearance. The aim of our study is to evaluate the effect of input function distortions on the myocardial perfusion as estimated by the model. To this end, we simulate noise-free myocardium time activity curves (TACs) with a two-compartment kinetic model. The input function to the model is a generic analytical function. Distortions of this function have been introduced by varying its parameters. Using the distorted input function, the compartment model has been fitted to the simulated myocardium TAC. This analysis has been performed for various sets of model parameters covering a physiologically relevant range. The evaluation shows that ±10% error in the input peak value can easily lead to ±10–25% error in the model parameter K 1, which relates to myocardial perfusion. Variations in the input function tail are generally less relevant. We conclude that an accurate estimation especially of the plasma input peak is crucial for a reliable kinetic analysis and blood flow estimation.

Human biokinetics of strontium. Part I: Intestinal absorption rate and its impact on the dose coefficient of 90Sr after ingestion

Intestinal absorption of strontium (Sr) in thirteen healthy adult German volunteers has been investigated by simultaneous oral and intravenous administration of two stable tracer isotopes, i.e. (84)Sr and (86)Sr. The measured Sr tracer concentration in plasma was analyzed using the convolution integral technique to obtain the intestinal absorption rate. The results showed that the Sr labeled in different foodstuffs was absorbed into the body fluids in a large range of difference. The maximum Sr absorption rates were observed within 60-120 min after administration. The rate of absorption is used to evaluate the intestinal absorption fraction, i.e. the f (1) value for various foodstuffs. The equivalent and effective dose coefficients for ingestion of (90)Sr were calculated using these f (1) values, and they were compared with those recommended by the International Commission on Radiological Protection (ICRP). The geometric and arithmetic means of the f (1) values are 0.38 and 0.45 associated with a geometric standard deviation and a standard deviation of 1.88 and 0.22, respectively. The 90% confidence interval of the f (1) values obtained in the present study ranges from 0.13 to 0.98. Expressed as the ratio of the 95 and 50% percentiles of the estimated probability, the uncertainty for the f (1) value corresponds to a factor of 2.58. The effective dose coefficients of (90)Sr after ingestion are 6.1 x 10(-9) Sv Bq(-1) for an f(1) value of 0.05, 1.0 x 10(-8) Sv Bq(-1) for 0.1, 1.9 x 10(-8) Sv Bq(-1) for 0.2, 2.8 x 10(-8) Sv Bq(-1) for 0.3, 3.6 x 10(-8) Sv Bq(-1) for 0.4, 5.3 x 10(-8) Sv Bq(-1) for 0.6, 7.1 x 10(-8) Sv Bq(-1) for 0.8, and 7.9 x 10(-8) Sv Bq(-1) for 0.9, respectively. Taking the effective dose coefficient of 2.8 x 10(-8) Sv Bq(-1) for an f (1) value of 0.3, which is recommended by the ICRP, as a reference, the effective dose coefficient of (90)Sr after ingestion varies by a factor of 2.8 when the f (1) value changes by a factor of 3, i.e. it decreases from 0.3 to 0.1 or increases from 0.3 to 0.9, respectively.

In-Vivo Imaging of Alzheimer Disease -Amyloid With [11C]SB-13 PET

In-vivo imaging of beta-amyloid plaques (Abeta) may improve both early detection of Alzheimer disease (AD) and efficacy assessment of new treatments for AD. The authors' aim was to develop a novel Abeta-specific positron-emission tomography (PET) tracer. Five female AD patients (54-77 years old) and six healthy female comparison subjects (53-74 years old), completed 2-hour PET scans after intravenous injection of 10 mCi of both the stilbene [11C]SB-13 and the benzothiazole [11C]6-OH-BTA-1 (also known as [11C]PIB). Kinetic analyses were performed on the resulting time-activity curves to derive Abeta binding-potential estimates, using as input function either the unmetabolized tracer concentration in venous plasma from a two-tissue compartment model or the density of radioactivity in the cerebellum. Authors compared the binding characteristics of the two radiotracers. The two radiotracers demonstrated similar binding properties with respect to regional distribution of retention (increased retention in the frontal and posterior temporal-inferior parietal association cortices in the AD patients, but not in the comparison subjects). Our preliminary PET data indicate that [11C]SB-13 may be similar to [11C]PIB in discriminating AD patients from comparison subjects. [11C]SB-13 is an effective PET tracer for fibrillar Abeta imaging in vivo, with similar performance as [11C]PIB. Future research directions include evaluation of tracer in larger AD patient samples and in subjects with amnestic mild cognitive impairment, evaluation of arterial input function, and comparison with other tracers, such as [18F]FDG as they relate to cognitive functioning.

Anesthesia-induced Alterations in Plasma Tracer Concentrations May Have Relevance for Brain Imaging Studies

Anesthesia-induced Alterations in Plasma Tracer Concentrations May Have Relevance for Brain Imaging Studies

Double isotope tracer method for measuring fractional zinc absorption: theoretical analysis.

Several approaches for estimation of fractional zinc absorption (FZA) by calculating the ratio of oral to intravenous stable isotopic tracer concentrations (at an appropriate time) in urine or plasma after their simultaneous administration have been proposed in the last decade. These simple-to-implement approaches, often referred to as the double isotopic tracer ratio (DITR) method, are more attractive than the classical "deconvolution" method and the more commonly used single-tracer methods based on fecal monitoring and indicator dilution, after oral or intravenous tracer administration, respectively. However, the domain of validity of DITR for measuring FZA has recently been questioned. In this paper, we provide a theoretical justification of the validity of four different "approximate" formulations of the DITR technique by demonstrating mathematically that their accuracy is a consequence of the particular properties of zinc kinetics.

Production and metabolic clearance of glucose under basal conditions in Type II (non-insulin-dependent) diabetes mellitus.

The pathogenesis of fasting hyperglycaemia in Type II (non-insulin-dependent) diabetes mellitus has yet to be clarified. Rates of glucose production (Ra), utilization and metabolic clearance rate were therefore measured during an extended fast, in control subjects and in Type II diabetic patients. Nine subjects with newly-diagnosed or diet-treated diabetes and seven control subjects matched for age and weight (BMI 36.0 +/- 2.4 and 35.3 +/- 3.1 kg/m2 respectively) underwent an overnight fast followed by a 10-h unprimed infusion of [6-3H]glucose. Plasma tracer concentrations were fitted by a single-compartment model. The metabolic clearance rate was near-constant [61.7 + 2.4 ml/(min-m2)] in diabetic patients and [75.5 +/- 3.3 ml/(min-m2)] in control subjects (p < 0.05). It was correlated to the glucose concentrations both at t = 0 (r = -0.752, p = 0.0008) and t = 10 h (r = -0.675, p = 0.004). The calculated volume of distribution was 17.3 +/- 1.4 l (18.2 % weight, diabetes), 19.6 +/- 2.4 l (18.4 % weight, control). Glycaemia fell from 10.7 +/- 0.8 mmol/l to 6.5 +/- 0.3 mmol/l by 10 h (p < 0.05) in diabetes and from 5.6 +/- 0.6 to 4.8 +/- 0.1 mmol/l in control subjects (p < 0.05). The rate of glucose production decreased in parallel, from 563 +/- 33 to 363 +/- 23 micromol/(min-m2) (p < 0.05) in diabetes from 419 +/- 20 to 347 +/- 32 micromol/(min-m2) in control subjects. Initial Ra was higher in diabetic patients than in control subjects (p < 0.05) and was highly correlated to glycaemia (r = 0.836, p = 0.0001). By 10 h, Ra had converged in diabetic patients and control subjects and all correlation with glycaemia was lost (r = 0.0017, p = 0.95). In relatively early diabetes, the more "labile" portion of fasting hyperglycaemia, which subsequently decreased, was closely related to the simultaneously decreasing Ra. The 25 % increase in glucose concentrations which persisted as stabilized Ra, resulted from about a 20 % lower metabolic clearance rate.