Compartmental Kinetic Analysis Research Articles

Inter-operator variability in compartmental kinetic analysis of 18F-fluoromisonidazole dynamic PET

PurposeTo assess the inter-operator variability in compartment analysis (CA) of dynamic-FMISO (dyn-FMISO) PET. MethodsStudy-I: Five investigators conducted CA for 23 NSCLC dyn-FMISO tumor time-activity-curves. Study-II: Four operators performed CA for four NSCLC dyn-FMISO datasets. Repeatability of Kinetic-Rate-Constants (KRCs) was assessed. ResultsStudy-I: Strong correlation (ICC > 0.9) and interchangeable results among operators existed for all KRCs. Study-II: Up to 103% variability in tumor segmentation, and weaker ICC in KRCs (ICC-VB = 0.53; ICC-K1 = 0.91; ICC-K1/k2 = 0.25; ICC-k3 = 0.32; ICC-Ki = 0.54) existed. All KRCs were repeatable among the different operators. ConclusionsInter-operator variability in CA of dyn-FMISO was shown to be within statistical errors.

Intermittent ischemia enhances the uptake of indocyanine green to livers subject to ischemia and reperfusion

Intermittent ischemia is known to promote post perfusion bile flow, and hence recovery of liver function following ischemia reperfusion of the liver. However, the mechanisms involved are not well understood. The aim of this study was to identify the step(s) in the bile acid transport pathway altered by intermittent ischemia. Arat model of segmental hepatic ischemia in which the bilateral median and left lateral lobes were made ischemic by clamping the blood vessels was used. Indocyanine green (ICG), infrared spectroscopy, and compartmental kinetic analysis, were used to indirectly monitor the movement of bile acids across hepatocytes in situ. Rates of bile flow were measured gravimetrically. In control livers (not subjected to ischemia), the movement of ICG from the blood to bile fluid could be described by a three compartment model comprising the blood, a rapidly-exchangeable compartment, and the hepatocyte cytoplasmic space. In livers subjected to continuous clamping, the rates of ICG uptake to the liver, and outflow from the liver, were greatly reduced compared with those in control livers. Intermittent clamping (three episodes of 15 min clamping) compared with continuous clamping substantially increased the rate of ICG uptake from the blood but had less effect on the rate of ICG outflow from hepatocytes. It is concluded that intermittent ischemia promotes post reperfusion bile flow in the early phase of ischemia reperfusion injury principally by enhancing the movement of bile acids from the blood to hepatocytes.

Incorporation of MRI-AIF Information For Improved Kinetic Modelling of Dynamic PET Data

In the analysis of dynamic PET data, compartmental kinetic analysis methods require an accurate knowledge of the arterial input function (AIF). Although arterial blood sampling is the gold standard of the methods used to measure the AIF, it is usually not preferred as it is an invasive method. An alternative method is the simultaneous estimation method (SIME), where physiological parameters and the AIF are estimated together, using information from different anatomical regions. Due to the large number of parameters to estimate in its optimisation, SIME is a computationally complex method and may sometimes fail to give accurate estimates. In this work, we try to improve SIME by utilising an input function derived from a simultaneously obtained DSC-MRI scan. With the assumption that the true value of one of the six parameter PET-AIF model can be derived from an MRI-AIF, the method is tested using simulated data. The results indicate that SIME can yield more robust results when the MRI information is included with a significant reduction in absolute bias of K <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">i</sub> estimates.

Evaluation of Quantitative Criteria for Glioma Grading With Static and Dynamic 18F-FDopa PET/CT

The aim of this study was to compare various acquisition and processing protocols for noninvasive glioma grading using either static or dynamic (18)F-FDopa PET. Dynamic studies were performed in 33 patients. Based on histopathological analysis, 18 patients had a high-grade (HG) tumor and 15 patients had a low-grade (LG) tumor. For static imaging, SUV(mean) and SUV(max) were calculated for different acquisition time ranges after injection. For dynamic imaging, the transport rate constant k1 was calculated according to a compartmental kinetic analysis using an image-derived input function. With the use of a 5-minute static imaging protocol starting at 38 minutes after injection, newly diagnosed HG tumors could be distinguished from LG tumors with a sensitivity of 70% and a specificity of 90% with a threshold of SUV(mean) of 2.5. In recurrent tumors, a sensitivity of 100% and a specificity of 80% for identifying HG tumors were obtained with a threshold set to 1.8. Dynamic imaging only slightly, but nonsignificantly, improved differential diagnosis. Static and dynamic imaging without blood sampling can discriminate between LG and HG for both newly diagnosed and recurrent gliomas. In dynamic imaging, excellent discrimination was obtained by considering the transport rate constant k1 of tumors. In static imaging, the best discrimination based on SUV was obtained for SUV(mean) calculated from a 5-minute acquisition started at 38 minutes after injection.

Analogue tracers and lumped constant in capillary beds

The lumped constant is a proportionality factor for converting a tracer analogue's metabolic rate to that of its mother substance. In a uniform system, it is expressed as the ratio of the tracer analogue's extraction fraction ( E ⁎) to the extraction fraction of its mother substance ( E). Here we show that, in capillary beds perfused by unidirectional blood flow, unequal concentration gradients of the tracer analogue and of the mother substance influence extraction fractions both locally and across the organ and that the direct proportionality of E ⁎ and E must be replaced by ln(1− E ⁎)/ln(1− E) to yield Λ, i.e. the lumped constant derived from first principles of bi-substrate enzyme and membrane kinetics. In other words, at a given capillary blood flow ( F), the ratio of systemic clearances (F E ⁎/FE), often used in compartmental kinetic analysis, must be replaced by the ratio of the intrinsic clearances, [− F ln(1− E ⁎)]/[− F ln(1− E)]. The conclusion is supported by 2-[ 18F]fluoro-2-deoxy- d-galactose removal kinetics in pig liver in vivo from previous publications by the dependence of E ⁎/ E and the independence of Λ, on blood galactose concentration. Moreover, our corrections to the results of compartmental kinetics are quantified for comparing extraction fractions in different regions of interest (e.g. by positron emission tomography) and for calculating Λ using whole-organ E ⁎ and E measured by arteriovenous concentration differences.

TU‐G‐211‐07: Combined NaF PET and FDG PET Based Assesment of Bone Metastasis Response after Chemotherapy Using Kinetic Analysis

Purpose: The differentiation between the residual tumor activity and the osseous reaction to the tumor is essential for therapy assessment of bone metastases. The 18‐F‐Sodium Fluoride (NaF) uptake reflects the osteoblastic process, while the FDG uptake reflects the tumor metabolism. The purpose of this study was to evaluate the assessment of treatment response with the kinetic analysis of concurrent NaF/FDG PET/CT images for specific clinical cases. Methods: Three prostate adenocarcinomas were treated with chemotherapy and imaged twice with NaF/FDG PET/CT: a baseline scan and a second scan after four weeks of chemotherapy. The NaF/FDG PET/CT imaging started with NaF injection, followed by 100 min dynamic PET imaging. Next, FDG was injected and followed by an additional 45 min of dynamic PET imaging. Macroparameters K_NaF and K_FDG (defined as K=K1×k3/(k2+k3)) were obtained by compartmental kinetic analysis. The accuracy of the kinetic parameter estimations was evaluated with simulations. Bone metastases were segmented (29 total). The ratio of mid‐therapy to pre‐therapy mean K_FDG and K_NaF parameters, which measured the response to therapy, was calculated for each metastasis. Results: The simulations revealed that the K_NaF and K_FDG estimations are highly correlated to the simulated value (r=0.9) while an estimated error is 50%. The K_FDG response and the K_NaF response are moderately correlated (r=0.7), but the mean K_FDG response over all the metastases is 0.7 while the mean K_NaF response is 0.9. The patterns in K_FDG and K_NaF parametric images are similar, but displaced and slightly distorted. Conclusions: Tumor metabolism and bone repair process can be imaged separately at the same time point using the presented imaging protocol, which was validated with simulations. The addition of FDG PET imaging to the osseous NaF PET imaging provides additional information to treatment response and has the potential to improve the assessment of bone metastasis in therapy.

Pharmacokinetic properties of indinavir in rat: some limitations of noncompartmental analysis

Background: Compartmental as well as noncompartmental analyses are used routinely in pharmacokinetic analysis. Materials and methods: Pharmacokinetic parameters of the anti-HIV agent, indinavir, have been determined in six male rats applying both the compartmental and the noncompartmental analysis. Results and discussion: A very slow declining phase was found in the indinavir plasma concentration profile using an extended sampling time period and applying a sensitive high-performance liquid chromatography assay method. This apparent terminal elimination phase can cause some significant errors when applying noncompartmental kinetic analysis to the data, with mean residence time (MRT) (544.2 ± 123.2 minutes), total systemic clearance (12.0 ± 2.1 mL/min/kg), and steady-state volume of distribution (Vd (ss)) (6.4 ± 1.0 L/kg) being highly different from the results of compartmental kinetic analysis (MRT, Cltotal, and Vd (ss) values of 23.7 ± 5.9 minutes, 35.18 ± 5.1 mL/min/kg, and 0.84 ± 0.28 L/kg, respectively). The parameters estimated by our noncompartmental approach were also significantly different from the results of the same type of data analysis reported in the literature. Conclusion: The differences in parameter estimations, while being a result of the extended plasma sampling period, which is recommended in noncompartmental analysis, support the priority of applying the compartmental analysis approach in the similar cases with some pre-assumptions, mainly ignoring the final apparent terminal elimination phase(s), very deep tissue, which involves very low drug concentrations.

Pharmacokinetics of enrofloxacin after single intravenous administration in sheep

The disposition of enrofloxacin in sheep was investigated after single-dose intravenous administration of 2.5 mg/kg body weight. Blood samples were drawn from the jugular vein at predetermined times after drug administration. Plasma concentrations of enrofloxacin and its active metabolite ciprofloxacin were simultaneously determined by reverse-phase high performance liquid chromatography. The data collected were subjected to non-compartmental and compartmental kinetic analysis. Statistical model theory was used to determine non-compartmental pharmacokinetic parameters. Disposition of enrofloxacin was described by a three-compartment open model with elimination from the central compartment following intravascular administration. The elimination half-life, the volume of distribution, and the area under the concentration vs time curve (AUC) were 4.31 h, 1.10 l/kg and 9.24 microg x h/ml, respectively. Enrofloxacin was metabolised to ciprofloxacin and the ratio between the AUCs of ciprofloxacin and enrofloxacin was 0.26 after intravenous administration. With predictive models of efficacy (maximum plasma concentrations/minimum inhibitory concentrations [Cmax/MIC] and AUC/MIC ratios in plasma) for most of the sheep pathogen microorganisms, enrofloxacin produced scores higher than 15 and 50, respectively. After intravenous administration atthe dose of 2.5 mg/kg, enrofloxacin achieved concentrations several times above the MIC for major pathogen bacteria in plasma, and it may prove useful in the treatment of infectious diseases caused by sensitive pathogens in sheep.

Pharmacokinetic properties of indinavir in rat: some limitations of noncompartmental analysis

Compartmental as well as noncompartmental analyses are used routinely in pharmacokinetic analysis. Pharmacokinetic parameters of the anti-HIV agent, indinavir, have been determined in six male rats applying both the compartmental and the noncompartmental analysis. A very slow declining phase was found in the indinavir plasma concentration profile using an extended sampling time period and applying a sensitive high-performance liquid chromatography assay method. This apparent terminal elimination phase can cause some significant errors when applying noncompartmental kinetic analysis to the data, with mean residence time (MRT) (544.2 +/- 123.2 minutes), total systemic clearance (12.0 +/- 2.1 mL/min/kg), and steady-state volume of distribution (V(d) (ss)) (6.4 +/- 1.0 L/kg) being highly different from the results of compartmental kinetic analysis (MRT, Cl(total), and V(d) (ss) values of 23.7 +/- 5.9 minutes, 35.18 +/- 5.1 mL/min/kg, and 0.84 +/- 0.28 L/kg, respectively). The parameters estimated by our noncompartmental approach were also significantly different from the results of the same type of data analysis reported in the literature. The differences in parameter estimations, while being a result of the extended plasma sampling period, which is recommended in noncompartmental analysis, support the priority of applying the compartmental analysis approach in the similar cases with some pre-assumptions, mainly ignoring the final apparent terminal elimination phase(s), very deep tissue, which involves very low drug concentrations.

Effects of monensin on volatile fatty acid metabolism in periparturient dairy cows using compartmental analysis

Eight multiparous periparturient Holstein cows fitted with ruminal cannulas were used in a split plot design to evaluate effects of monensin on ruminal volatile fatty acid (VFA) metabolism. Diets were supplemented with 300 mg/day of monensin, or no monensin, both prepartum and postpartum. Isotopic tracers, Na-1- 13C-acetate (Ac), Na-1- 13C-propionate (Pr), or Na-1- 13C-butyrate (Bu) were used as markers to describe VFA kinetics in the rumen. The Windows version of SAAM software (WinSAAM) was used to develop a steady state VFA model. A 9-compartment model was adequate to comprehensively describe ruminal VFA metabolism. The main VFA compartments consisted of Ac, Pr and Bu. The model estimated lower Bu and Ac interconversions with monensin, postpartum (Bu to Ac; 0.14 versus 0.12; P=0.04, and Ac to Bu; 0.32 versus 0.25; P=0.11) compared to when measured prepartum. Results demonstrate that dilution studies employing stable isotopes of VFA can be used to provide information on VFA metabolism of the periparturient dairy cow. A time frame of 320 min of labeled VFA infusion employing a single injection allows accurate quantification of VFA metabolism in the rumen. Compartmental kinetic analysis of major VFA in the rumen indicate that monensin reduced about 0.125 the portion of the Ac that contributes to Bu by reducing movements of Bu originated carbons to the Ac pool. Monensin may affect certain biochemical pathways of interconversion of Bu and Ac in the rumen. Propionate kinetic data suggests that Pr behaves as a single pool in the rumen. Monensin did not affect Pr production in the rumen suggesting that monensin improves the metabolic status of the transition cow in a way other than increasing Pr production in the rumen.

Quantitative analysis of donepezil binding to acetylcholinesterase using positron emission tomography and [5-11C-methoxy]donepezil

The aim of this study was to establish kinetic analysis of [5-11C-methoxy]donepezil ([11C]donepezil), which was developed for the in-vivo visualization of donepezil binding to acetylcholinesterase (AChE) using positron emission tomography (PET). Donepezil is an AChE inhibitor that is widely prescribed to ameliorate the cognitive impairment of patients with dementia. Six healthy subjects took part in a dynamic study involving a 60-min PET scan after intravenous injection of [11C]donepezil. The total distribution volume (tDV) of [11C]donepezil was quantified by compartmental kinetic analysis and Logan graphical analysis. A one-tissue compartment model (1TCM) and a two-tissue compartment model (2TCM) were applied in the kinetic analysis. Goodness of fit was assessed with χ2 criterion and Akaike's Information Criterion (AIC). Compared with a 1TCM, goodness of fit was significantly improved by a 2TCM. The tDVs provided by Logan graphical analysis were slightly lower than those provided by a 2TCM. The rank order of the mean tDVs in 10 regions was in line with the AChE activity reported in a previous post-mortem study. Logan graphical analysis generated voxel-wise images of tDV, revealing the overall distribution pattern of AChE in individual brains. Significant correlation was observed between tDVs calculated with and without metabolite correction for plasma time–activity curves, indicating that metabolite correction could be omitted. In conclusion, this method enables quantitative analysis of AChE and direct investigation of the pharmacokinetics of donepezil in the human brain.

Modulation of [ 18F]fluorodopa (FDOPA) kinetics in the brain of healthy volunteers after acute haloperidol challenge

In animal studies, acute antipsychotic treatment was shown to enhance striatal DOPA-decarboxylase (DDC) activity. However, this phenomenon has not been demonstrated in humans by positron emission tomography (PET). Therefore, we investigated acute haloperidol effects on DDC activity in humans using [ 18F]fluorodopa (FDOPA) PET. Nine healthy volunteers were scanned with FDOPA in drug-free baseline conditions and after 3 days of haloperidol treatment (5 mg/day). A continuous performance test (CPT) was administered in both conditions. The net blood–brain clearance of FDOPA ( K in app) in striatum, mesencephalon, and medial prefrontal cortex was calculated by volume-of-interest analysis. The macroparameter K in app is a composite of several kinetic terms defining the distribution volume of FDOPA in brain ( V e D) and the relative activity of DOPA decarboxylase ( k 3 D). Therefore, compartmental kinetic analysis was used to identify the physiological basis of the observed changes in K in app period. The magnitude of K in app was significantly increased in the putamen (18%) and mesencephalon (36%). Furthermore, V e D in the brain was increased by 15%. Increments of k 3 D in the basal ganglia did not attain statistical significance. The significant worsening of CPT results did not correlate with changes in FDOPA utilization. The present PET results indicate potentiation of FDOPA utilization in human basal ganglia by acute haloperidol treatment, apparently due to increased availability throughout the brain. The stimulation of DDC cannot be excluded due to insufficient statistical power in the estimation of k 3 D changes.

Age-related changes in the pharmacokinetics of marbofloxacin after intravenous administration in goats.

The pharmacokinetics of marbofloxacin was studied in adult goats and 1-, 3- and 6-weeks-old kids after single dose i.v. dose of 2 mg/kg body weight. Drug concentration in plasma was determined by high-performance liquid chromatography (HPLC) and the data collected were subjected to compartmental kinetic analysis. Volume of distribution was relatively high in adult goats (Vss = 1.31 L/kg), and increased with age (Vss = 0.92 L/kg, 0.95 L/kg and 1.00 L/kg, in 1-, 3- and 6-weeks-old kids respectively). Total body clearance (Cl) also increased with age from 0.080 L/kg.h (1-week-old) to 0.097 L/kg.h (3-weeks-old), 0.18 L/kg.h (6-weeks-old) and 0.23 L/kg.h (adult goats). As a consequence of increased body Cl, area under the plasma concentration vs. time curve decreased with age (AUC = 27.46 microg.h/mL, 22.61 microg.h/mL, 11.86 microg.h/mL and 8.44 microg.h/mL in 1-, 3-, 6-weeks-old kids and adults, respectively) and a longer elimination half-life was found during the first 3 weeks of age (t1/2beta = 9.66 h, 8.25 h, 6.44 h and 7.18 h, in 1-, 3-, 6-weeks-old kids and adults, respectively). Mean residence time decreased with age from 11.86 h in 1-week-old kids to 9.63 h (3 weeks), 5.76 h (6 weeks) and 5.06 h in adult goats.

A Kinetic Evaluation of the Absorption, Efflux, and Metabolism of Verapamil in the Autoperfused Rat Jejunum

P-glycoprotein (P-gp)-mediated drug efflux from the apical membrane of enterocytes is believed to modulate intestinal cytochrome P450 3A (CYP3A) metabolism by altering substrate access to the CYP3A enzyme. This interplay between P-gp and CYP3A was investigated in a rat in situ model of intestinal permeation, where a recirculating luminal perfusion of the jejunum was coupled with mesenteric vein blood collection to simultaneously monitor the uptake, transport, and metabolism of the P-gp and CYP3A substrate, verapamil. Transport of intact verapamil into the venous blood was increased by 160, 84, and 160%, and the intestinal extraction ratio on passage across the jejunum was reduced by 15, 24, and 97% by inhibitors of P-gp [PSC833 ([3'-keto-Me-Bmt(1)]-[Val(2)]-cyclosporin)], CYP3A (midazolam), or P-gp and CYP3A (ketoconazole), respectively, when present in the luminal perfusate and compared with control experiments. Compartmental kinetic analysis of the data revealed that inhibition of P-gp did not affect the rate constant describing verapamil metabolism but, rather, increased the intestinal uptake of verapamil and stimulated a disproportionate increase in verapamil transport into the venous blood. The increase in verapamil transport, in the absence of changes to metabolism, reduced the intestinal extraction ratio. This finding may be explained by saturation of intracellular verapamil binding sites within the intestinal tissue in response to increased verapamil uptake resulting from P-gp inhibition. The current findings confirm previous in vitro and theoretical approaches which suggest that P-gp can modulate the extent of intestinal extraction of P-gp/CYP3A substrates.

Measurement of 3-methylhistidine production in lambs by using compartmental-kinetic analysis

The kinetics of 3-methylhistidine (3MH) metabolism in four crossbred lambs were studied. Each lamb was injected with an intravenous dose of 3-[2H3]methylhistidine (d3-3MH) and the stable isotope disappearance in plasma and appearance in both urine and muscle were measured. Immediately after the administration of tracer there was a phase of rapid disappearance of tracer from the plasma, which was followed by a more gradual decrease in d3-3MH from the plasma during the last 4 d of the experiment. A minimum of three exponentials was required to describe the plasma decay curve adequately. The kinetic model of 3MH in the whole animal was constructed by using the SAAM/CONSAM computer modelling program. Two different configurations of a three-compartment model are described: (1) a simple three-pool model, in which plasma kinetics were entered into pool 1 out of which they had one undefinable exit; (2) a plasma-urinary three-pool model with two exits, in which the urinary kinetics were entered as an exit out of pool 1 and required a second exit out of pool 3 to produce an adequate fit. In addition, muscle kinetics from biopsies of the longissimus dorsi were entered into either pool 2 or 3 using the plasma-urinary model. Steady-state mass and transport rate values were obtained for each model construct described, and a de novo production rate corresponding to a fractional breakdown rate of myofibrillar protein of approximately 5%/d was also calculated. The model predicted that only 15% of 3MH was excreted in urine as free 3MH, which is consistent with current knowledge of 3MH excretion in sheep. The simple three-pool plasma kinetic model, therefore, could be used to estimate, by a relatively simple injection-sampling technique, the extent of muscle protein turnover in lambs.

Insulin removal in man: in vivo evidence for a receptor-mediated process.

To evaluate the in vivo participation of insulin receptors in both hepatic and extrahepatic removal of insulin, compartmental kinetic analysis of insulin behavior was performed in a patient with blocked receptors due to endogenous antiinsulin receptor antibodies. Using the standard three-compartment simulation of insulin behavior, the responses to both a 5-U injection of exogenous insulin and a 4.2-U secretion of endogenous insulin subsequent to tolbutamide injection were examined. In response to both exogenous and endogenous insulin, hepatic removal of insulin was reduced to less than 18% of the insulin exposure (normal, 40-60%). The metabolic clearance of insulin was reduced from the normal level of 520 ml/min to less than 120 ml/min, consistent with a reduction in receptor-mediated removal of insulin from the blood. These studies propose quantitative parameters for insulin receptor function in hepatic and extrahepatic removal of insulin in man.

Stochastic models for tracer experiments in the circulation III. The lumped catenary system

The theory of the dispersion of indicator substances injected into the blood has been analyzed in the past from two apparently different viewpoints. On one side, the distribution of transit times through the circulatory labyrinth has been discussed as a stochastic process and, on the other, by application of compartmental kinetic analysis. The frequency function for transit times P( t) possesses moments which can be expressed in terms of coefficients of a power-series expansion near λ = 0 of the Laplace transform L (λ) of P( t). By treating the compartmental case as a finite birth and death process it is shown that the infinity of stochastic states of the classical random walk can be approximated by lumping the states into a few sets of equivalent ones, yielding an approximate frequency function P n (t A method is presented whereby, through matching of moments of P n (t and P( t) or their transforms near λ = 0, the best approximation can be made. Results for the classical random walk and for a lumped five-compartment and a three-compartment system are compared. The similarity in the three cases explains the often observed fact that fairly good representations of physiological indicator-dilution curves can be obtained by the use of lumped hydraulic and electrical analogs. A general principle of lumping in catenary tracer-kinetic systems is established.