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PubMed2006

Kinetic model for studying the effect of quercetin on cholesterol oxidation during heating.

Inhibition of the heat-induced cholesterol oxidation at 150 degrees C by incorporation of quercetin was kinetically studied. Results showed that without quercetin, the cholesterol oxidation products (COPs) concentration increased with increasing heating time. A low amount (0.002%, w/w) of quercetin was effective in inhibiting the formation of COPs during the initial heating period (< or =30 min) at 150 degrees C. However, after prolonged heating (30-120 min), a low antioxidant activity was observed because of the degradation of quercetin. When using nonlinear regression models for kinetic study of cholesterol oxidation in the absence of quercetin, the epoxidation showed the highest rate constant (h(-1) = 683.1), followed by free radical chain reaction (h(-1) = 453.5), reduction (h(-1) = 290.3), dehydration (h(-1) = 155.5), triol dehydrogenation (h(-1) = 5.35), dehydrogenation (h(-1) = 0.68), thermal degradation (h(-1) = 0.66), and triol formation (h(-1) = 0.38). However, in the presence of quercetin, the reaction rate constants (h(-1)) for epoxidation (551.4), free radical chain reaction (111.7), and thermal degradation (0.28) were reduced greatly. The kinetic model developed in this study can be used to predict the inhibition of COPs by quercetin during the heating of cholesterol.

Cholesterol↗
PubMed1984

Tracer kinetic model of blood-brain barrier transport of plasma protein-bound ligands. Empiric testing of the free hormone hypothesis.

Previous studies have shown that the fraction of hormone or drug that is plasma protein bound is readily available for transport through the brain endothelial wall, i.e., the blood-brain barrier (BBB). To test whether these observations are reconcilable with the free-hormone hypothesis, a tracer-kinetic model is used in the present investigations to analyze in vivo initial extraction data on BBB transport of protein-bound steroid hormones (dihydrotestosterone, testosterone, estradiol, and corticosterone), thyroid hormones (triiodothyronine), and lipophilic amine drugs (propranolol). The plasma proteins used are bovine albumin and human orosomucoid. Transport data was fit to a modification of the Kety-Renkin-Crone equation of capillary physiology; the modified equation incorporates the principles of both capillary physiology and plasma protein-ligand mass action binding relationships. In most cases, the experimental data is best fit to the model equation when the apparent in vivo dissociation constant, KDa, of the ligand protein binding reaction increases to values that are 5- to 50-fold greater than the in vitro dissociation constant, KD. This result indicates that the rate of ligand dissociation from the plasma protein is accelerated in the capillary bed relative to the in vitro situation. It is hypothesized that the major factor leading to the rapid transport in vivo of protein-bound ligands into tissues such as brain is an endothelial-induced decrease in the affinity of the plasma protein for the ligand. Under these conditions, the amount of plasma ligand available for tissue clearance in vivo parallels the protein-bound fraction, not the free hormone.

Animals↗
PubMed2002

Tabletting of pellet-matrix systems: ability of parameters from dynamic and kinetic models to elucidate the densification of matrix formers and of pellets.

Two different types of pellets, i.e. drug-free sugar spheres, and pellets, spray-layered with crystalline theophylline and coated with Eudragit RS/RL, were tabletted each in combination with matrix-forming powder mixtures of Avicel PH200 and PEG 4000. The die fills from pellets and powder mixtures were regarded as two-compartment systems with a volume fraction of the pellets being limited to 0.52 corresponding to a cubic lattice, and the maximum degrees of densifications were adjusted related to the matrix. To data measured during single compression cycles on an instrumented eccentric tabletting machine and transformed appropriately, the Kawakita equation, the Heckel function, and a modified Weibull function were fitted, and the total work of compression was calculated. The Kawakita model fitted well systems with both types of pellets. Its parameters reflected the additional densification of the theophylline pellets separately from that of the matrix formers. The Heckel function could only be applied to systems containing non-porous sugar spheres, since the theophylline pellets underwent considerable densification and deformation. Only, when the Heckel porosity function was related to the volume fraction of the matrix, excluding the sugar spheres, the approximately linear regions for mixtures with increasing volume proportions of sugar spheres occured in comparable regions of densification. Parameters of the modified Weibull function demonstrated an increasing resistance against densification with increasing amounts of pellets. The total work of compression increased steeply with increasing volume fractions for pellets from 0.42 to 0.46 indicating, that the resistance against densification already rose when the pellets were still isolated. In conclusion, the combination of dynamic and kinetic models provides a comprehensible insight into the process of tabletting powder mixtures with pellets. Particularly, the Kawakita model was a suitable tool to differentiate the actual changes in porosity during compression from the compressibility of such complex systems.

Compressive Strength↗
PubMed2006

Evaluation of tracer kinetic models for quantification of P-glycoprotein function using (R)-[11C]verapamil and PET.

Diminished P-glycoprotein (P-gp)-mediated transport across the blood-brain barrier may play an important role in several neurodegenerative disorders. In previous studies, a racemic mixture of (R)-[(11)C]verapamil and (S)-[(11)C]verapamil has been used as tracer for assessing P-gp function using positron emission tomography (PET). Quantification, however, is compromised by potential differences in kinetics between these two isomers. The aim of the present study was to evaluate the kinetics of pure (R)-[(11)C]verapamil in humans and to develop a tracer kinetic model for the analysis of P-gp-mediated transport of (R)-[(11)C]verapamil, including the putative contribution of its radioactive metabolites. Dynamic (R)-[(11)C]verapamil PET scans of 10 male volunteers were analysed with various single- or two-tissue compartment models, with separate compartments for N-dealkylated and N-demethylated metabolites, assuming that either (R)-[(11)C]verapamil alone or (R)-[(11)C]verapamil and any combination of metabolites cross the BBB. In addition, six of the subjects underwent two (R)-[(11)C]verapamil scans to evaluate test-retest reliability. One hour after injection, 50% of total plasma radioactivity consisted of labelled metabolites. Most models fitted the data well and the analysis did not point to a definite 'best' model, with differences in optimal model between subjects. The lowest mean test-retest variability (2.9%) was found for a single-tissue model without any metabolite correction. Models with separate metabolite compartments lead to high test-retest variability. Assuming that differences in kinetics of (R)-[(11)C]verapamil and N-dealkylated metabolites are small, a one input, one-tissue model with correction for N-demethylated metabolites only leads to a good compromise between fit quality and test-retest variability.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Accumulation and toxicity of cadmium in the aquatic oligochaete Tubifex tubifex: a kinetic modeling approach.

Heavy metal pollution is a serious threat to ecosystem functioning. Different approaches have been developed to relate the exposure of heavy metals to their accumulation and toxicity. One approach is to relate metal toxicity to the concentrations of the metals in the whole body or a specific target tissue instead of the external exposure concentrations. To test the usefulness of this approach, the relationship between cadmium exposure, accumulation, and toxicity was investigated using an oligochaete worm and kinetic modeling. The uptake and elimination of cadmium by the aquatic oligochaete Tubifex tubifex from the aqueous phase was studied as function of time at different exposure concentrations using both radioactive and non-radioactive cadmium. A two-compartmental pharmacokinetic model was constructed and parametrized by fitting the model to the measured cadmium body concentrations during exposure to different cadmium concentrations. The uptake rate constants were dependent on the cadmium exposure concentration, and this relation could be well-described by incorporation of Michaelis-Menten type uptake kinetics. The toxicity of cadmium was analyzed by determining the lethal exposure concentration associated with a mortality of 50% (LC50) at different time points. LC50 values decreased with increasing exposure time reaching the incipient lethal level after 15 d. Critical body concentrations (CBC) associated with 50% mortality were calculated by combining the model-predicted pharmacokinetic parameters and the measured LC50 values. The predicted mean CBC (0.32 micromol/g wet weight +/- 0.02) was in good agreement with the experimentally obtained CBC for cadmium found in T. tubifex (0.37 micromol/g wet weight +/- 0.07) and appeared to be independent of exposure time and exposure concentration. Our results show that a pharmacokinetic modeling approach provides a tool to link metal exposure to availability, accumulation, and toxicity under variable exposure scenarios taking into account the kinetics of the processes.

Animals↗
PubMed1979

The discrete-time kinetic model analysis of DNA content distributions in experimental tumour cells.

A method was developed to analyse and characterize FMF measurements of DNA content distribution, utilizing the discrete time kinetic (DTK) model for cell kinetics analysis. The DTK model determines the time sequence of the cell age distribution during the proliferation of a tumor cell population and simulates the distribution pattern of the DNA content of cells in each age compartment of the cell cycle. The cells in one age compartment are distributed and spread into several compartments of the DNA content distribution to allow for different rates of DNA synthesis and instrument dispersion effects. It is assumed that the DNA content of cells in each age compartment has a Gaussian distribution. Thus, for a given cell age distribution the DNA content distribution depends on two parameters of the cells in each age compartment: the average DNA content and its coefficient of variation. As the DTK model generates the best fit DNA content distribution to the FMF measurement data, it enables one to estimate specific values of these two parameters in each stage of the cell cycle and to determine the fraction of cells in each cycle phase. The method was utilized to fit FMf measurements of DNA content distributions and to analyse their relationship tothe cell kinetic parameters, namely cell loss rate, cell cycle times and grwoth graction of exponentially growing Chinese hamster ovary cells in vitro and, also, with a wide range of coeffficients of variation, of the L1210 ascites tumour during the growth period.

Cell Cycle↗
PubMed1993

Use of a biophysical-kinetic model to understand the roles of protein binding and membrane partitioning on passive diffusion of highly lipophilic molecules across cellular barriers.

The novel antioxidants U-78517F and U-74006F, or lazaroids, are highly lipophilic organic molecules with poor brain uptake. To understand this paradoxical behavior better, continuous monolayers of Madin-Darby canine kidney (MDCK) epithelial cells with distinct apical (AP) and basolateral (BL) plasma membrane domains grown on polycarbonate membrane filters and plastic were used to examine the mechanism of transcellular diffusion. Independent kinetic experiments were used to quantify AP to BL flux, efflux from the AP and BL membranes and AP membrane partitioning as functions of bovine serum albumin (BSA) concentration. Fluxes were appropriately reduced to permeability coefficients (Pe) for the membrane, aqueous boundary layer (ABL) and filter, BSA-drug binding constants, and effective (Ke) and intrinsic (Kintr) membrane partition coefficients in the absence of metabolism. Both Pe and Ke decreased exponentially with increased BSA concentration and a concomitant decrease in free drug concentration. Uptake was ABL-controlled under the conditions used and its Pe was 1,000-fold faster than that for efflux due to a large Kintr. Therefore, diffusion across the cellular barrier was limited kinetically by the equilibrium between protein-bound drug and free drug partitioned into the cell membrane and the rate-limiting desorption of drug from the cell membrane into the aqueous receiver. This suggests that brain uptake of these lipophilic antioxidants is limited by interactions with plasma proteins and, possibly, by unfavorable partitioning from the endothelium into the underlying tissue. The present biophysical kinetic model is proposed as generally useful in studying the penetrative ability of other membrane interacting molecules.

Animals↗
PubMed1999

Two-dimensional kinetic models for radiotherapy planning quality assurance.

For treatment planning, the visualization of the direction and orientation of a beam, specified by a set of machine angles, can sometimes be very difficult. A set of simple two-dimensional kinetic models has been prepared. These show the angular and field conventions of the local linear accelerators.

Audiovisual Aids↗
PubMed1982

Radiation-induced inactivation of superoxide dismutase in nitrous oxide-saturated solutions. A kinetic model.

It has been reported that the inactivation yield of superoxide dismutase from bovine erythrocytes irradiated in N2O-saturated solutions increases exponentially with the initial enzyme concentration and that dose-response curves are non-exponential. The present work analyses these data using a kinetic model which indicates that the inactivation process is a second order reaction and that the reactivities of the active (Ea) and inactive (Ei) enzymes toward hydroxyl radical (.OH) are unequal. The calculated rate constants for the reactivities of Ea and Ei with .OH are 2.54 . 10(10) M-1 . s-1, respectively. The ratio between number of collisions and inactivation events is estimated at 20, in good agreement with a previous report. This model suggests that subunit exchange processes play an important role in the inactivation reaction.

Animals↗
PubMed2003

Monitoring the formation and decay of transient photosensitized intermediates using pump-probe UV resonance Raman spectroscopy. II: Kinetic modeling and multidimensional least-squares analysis.

Analysis of transient excited-state Raman spectra is a challenging spectroscopic measurement since transient spectral features are often overlapped with dominant ground-state and solvent bands. In the previous manuscript, resolution of component Raman spectra from the time-resolved amine quenching of excited-triplet benzophenone was accomplished using self-modeling curve resolution, a model-free factor analysis technique that relies on correlation in the data along a changing composition dimension. The results are consistent with the production of diphenylketyl radicals by H-atom abstraction from the amine and subsequent free-radical decay by recombination reactions. A kinetic model for this chemistry is developed in the present work, based on the observed Raman scattering data and the structures of product species confirmed by mass spectral analysis. The model is applied to the analysis of the time-dependent Raman scattering data using multidimensional least-squares methods, and it yielded well-resolved spectra of benzophenone excited-triplet states, diphenyl ketyl radical, and the solvent and ground-state precursors. The best-fit kinetic parameters agree well with the time-dependent triplet-state and ketyl-radical concentration profiles.

Algorithms↗
PubMed2003

Spontaneous aggregation and cytotoxicity of the beta-amyloid Abeta1-40: a kinetic model.

The time dependency of the spontaneous aggregation of the fibrillogenic beta-amyloid peptide, Abeta1-40, was measured by turbidity, circular dichroism, HPLC, and fluorescence polarization. The results by all methods were comparable and they were most consistent with a kinetic model where the peptide first slowly forms an activated monomeric derivative (AM), which is the only species able to initiate, by tetramerization, the formation of linear aggregates. The anti-Abeta antibody 6E10, raised against residues 1-17, at concentrations of 200-300 nM delayed significantly the aggregation of 50 microM amyloid peptide. The anti-Abeta antibody 4G8, raised against residues 17-24, was much less active in that respect, while the antibody A162, raised against the C-terminal residues 39-43 of the full-length Abeta was totally inactive at those concentrations. Concomitant with the aggregation experiments, we also measured the time dependency of the Abeta1-40-induced toxicity toward SH-EPI cells and hippocampal neurons, evaluated by SYTOX Green fluorescence, lactate dehydrogenase release, and activation of caspases. The extent of cell damage measured by all methods reached a maximum at the same time and this maximum coincided with that of the concentration of AM. According to the kinetic scheme, the latter is the only transient peptide species whose concentration passes through a maximum. Thus, it appears that the toxic species of Abeta1-40 is most likely the same transient activated monomer that is responsible for the nucleation of fibril formation. These conclusions should provide a structural basis for understanding the toxicity of Abeta1-40 in vitro and possibly in vivo.

Amyloid beta-Peptides↗
PubMed1999

Sigmoidal kinetic model for two co-operative substrate-binding sites in a cytochrome P450 3A4 active site: an example of the metabolism of diazepam and its derivatives.

Cytochrome P450 3A4 (CYP3A4) plays a prominent role in the metabolism of a vast array of drugs and xenobiotics and exhibits broad substrate specificities. Most cytochrome P450-mediated reactions follow simple Michaelis-Menten kinetics. These parameters are widely accepted to predict pharmacokinetic and pharmacodynamic consequences in vivo caused by exposure to one or multiple drugs. However, CYP3A4 in many cases exhibits allosteric (sigmoidal) characteristics that make the Michaelis constants difficult to estimate. In the present study, diazepam, temazepam and nordiazepam were employed as substrates of CYP3A4 to propose a kinetic model. The model hypothesized that CYP3A4 contains two substrate-binding sites in a single active site that are both distinct and co-operative, and the resulting velocity equation had a good fit with the sigmoidal kinetic observations. Therefore, four pairs of the kinetic estimates (KS1, kalpha, KS2, kbeta, KS3, kdelta, KS4 and kgamma) were resolved to interpret the features of binding affinity and catalytic ability of CYP3A4. Dissociation constants KS1 and KS2 for two single-substrate-bound enzyme molecules (SE and ES) were 3-50-fold greater than KS3 and KS4 for a two-substrate-bound enzyme (SES), while respective rate constants kdelta and kgamma were 3-218-fold greater than kalpha and kbeta, implying that access and binding of the first molecule to either site in an active pocket of CYP3A4 can enhance the binding affinity and reaction rate of the vacant site for the second substrate. Thus our results provide some new insights into the co-operative binding of two substrates in the inner portions of an allosteric CYP3A4 active site.

Adult↗
PubMed1994

[Clinical evaluation of kinetic model for the quantification of liver function with Tc-99m PMT and dynamic scintigraphy].

The purpose of this study was to quantify the uptake and excretion of Tc-99m-N-pyridoxyl-5-methyltryptophan (PMT) by hepatocytes using a tracer kinetic modeling approach, and to clarify the pathophysiological changes of diffuse parenchymal liver diseases. Fifty-two patients with liver diseases and seven normal subjects were studied. Studies were performed using an intravenous bolus injection of 185 MBq of PMT. Our compartment model consisted of three compartments. These parameters were calculated using the non-linear least-square method. The fitting curves agreed well with the measured ones. K1 correlated with blood tests of liver function better than parameters from the two-compartment model such as ku. K1 correlated especially closely with K-ICG (r = 0.898). K1 reflected hepatic blood flow, and the decrease of K1 was associated with hepatic dysfunction. Although K3 correlated poorly with serum bilirubin (r = -0.447), it correlated well with MTT (deconvolutional analysis) (r = -0.833). K3 reflected excretory function, and did not decrease until liver function was moderately damaged. By using three-compartment analysis, we were better able to explain the pathophysiological status of the liver. Our model is more useful for the assessment of liver function than the simple model.

Adult↗
PubMedDate not supplied

Effects of different sampling methods for measurement of post dialysis blood urea nitrogen on urea kinetic modeling derived parameters in patients undergoing long-term hemodialysis.

A simple and reliable sampling method for measuring post-dialysis blood urea nitrogen (C2) has not been well established. Therefore, the effects of different methods of sampling C2 on calculating urea kinetic modeling (UKM) derived parameters were studied in patients on hemodialysis. At first, C2 values were sampled at the end of hemodialysis at a blood flow rate of 300 ml per min (blood flow rate (Qb) 300 ml per min). They were then divided into two groups. In group 1 (n = 11), C2 samples were taken after slowing down Qb to 100 ml per min for 3 min (C2-100); the blood pump was then stopped for 1 min, and C2 was again sampled (C2-100-stop). Finally, C2 was sampled with Qb restored to 100 ml per min and the venous line clamped for another 12 sec (C2-100-clamp). In group 2 (n = 11), C2 samples were collected after Qb was slowed down to 50 ml per min for 3 min (C2-50), and C2-50-stop was then measured. Finally, C2-50-clamp was measured. Using C2-clamp as a reference standard, UKM parameters were calculated using a variable volume, single pool UKM. The authors found that Kt/V calculated by C2-300, C2-100, and C2-50 overestimated the reference Kt/V by 8.4-9.1%, 5.1%, and 3%, respectively. In contrast, protein catabolic rate and time-averaged BUN were affected only minimally. Therefore, a low flow technique with a Qb of 50 ml per min for 3 min can be used for the routine estimation of C2 and UKM-derived parameters with reasonable accuracy.

Blood Flow Velocity↗
PubMed1988

[A kinetic model of the interaction of stable GTP analogs with a system of opioid receptors].

The effect of a stable GTP analog, GppNp, on the agonist binding to rat brain opioid receptors was studied. It was shown that the nucleotide used at low concentrations activates, and at high concentrations inhibits the ligand interaction with the mu-, delta- and kappa-receptors. The inhibiting effect of GppNp on the formation of the morphine and D-Ala2, D-Leu5-enkephalin complexes with high affinity opioid receptor binding sites is due to the decrease of the ligand affinity for the corresponding sites. A kinetic model of the GppNp effect on high affinity binding sites stipulating that in the course of nucleotide binding the GTP-binding protein dissociates and that the N-protein alpha-subunits thereby formed are liberated into the surrounding solution, was proposed. It was demonstrated that GppNp can modulate the properties of opioid receptors in the absence of the ligand in a system and the inhibiting effect of GppNp depends on the concentration of membrane preparation.

Animals↗
PubMed2005

A kinetic modeling of chondrocyte culture for manufacture of tissue-engineered cartilage.

For repairing articular cartilage defects, innovative techniques based on tissue engineering have been developed and are now entering into the practical stage of clinical application by means of grafting in vitro cultured products. A variety of natural and artificial materials available for scaffolds, which permit chondrocyte cells to aggregate, have been designed for their ability to promote cell growth and differentiation. From the viewpoint of the manufacturing process for tissue-engineered cartilage, the diverse nature of raw materials (seeding cells) and end products (cultured cartilage) oblige us to design a tailor-made process with less reproducibility, which is an obstacle to establishing a production doctrine based on bioengineering knowledge concerning growth kinetics and modeling as well as designs of bioreactors and culture operations for certification of high product quality. In this article, we review the recent advances in the manufacturing of tissue-engineered cartilage. After outlining the manufacturing processes for tissue-engineered cartilage in the first section, the second and third sections, respectively, describe the three-dimensional culture of chondrocytes with Aterocollagen gel and kinetic model consideration as a tool for evaluating this culture process. In the final section, culture strategy is discussed in terms of the combined processes of monolayer growth (ex vivo chondrocyte cell expansion) and three-dimensional growth (construction of cultured cartilage in the gel).

Animals↗
PubMed2001

Kinetic model for the fate of 6-[18F]fluorodopamine in the human heart: a novel means to examine cardiac sympathetic neuronal function.

After injection of 6-[18F]fluorodopamine, thoracic positron emission tomographic scanning visualizes the sympathetic innervation of the heart. This report introduces a kinetic model that relates 6-[18F]fluorodopamine positron emission tomographic scanning results to specific aspects of cardiac sympathoneural function. Inputs were the 6-[18F]fluorodopamine concentration in arterial blood and the estimated contribution of circulating metabolites of 6-[18F]fluorodopamine. All of the three compartments in the model were intraneuronal. Two compartments corresponded to vesicles in sympathetic nerves, consistent with the "multiple vesicular pool" hypothesis from preclinical studies. The model successfully fit the empirical time-activity curve for myocardial 6-[18F]fluorodopamine-derived radioactivity and predicted correctly the effects of several neuropharmacological and physiological manipulations on the time-activity curve. Myocardial cell uptake of metabolites of 6-[18F]fluorodopamine from the circulation could explain an immediate peak of 6-[18F]fluorodopamine-derived radioactivity. The model seems useful in predicting effects of altered cardiac sympathetic function on time-activity curves for myocardial 6-[18F]fluorodopamine-derived radioactivity in humans.

Adrenergic Fibers↗
PubMed2001

A kinetic model for a biopanning process considering antigen desorption and effective antigen concentration on a solid phase.

A phage display library is a powerful tool for screening ligands such as antibodies and peptides that specifically recognize a target. In this study, we established a kinetic model describing the affinity selection process of phage display libraries and verified the model experimentally. Desorption of target molecules from a solid phase and orientation of the epitopes of adsorbed target molecules are taken into account in this model. The ratio of the effective antigen density to the total antigen density was estimated to be 0.0127(+/-)0.0018 when bovine pancreatic ribonuclease A (RNase A) adsorbed on polystyrene beads was recognized by an anti-RNase A single-chain Fv phage antibody. The model can faithfully describe the recovery of the phage antibody in a round of biopanning based on the effective concentration of RNase A on the beads, the desorption rate constant of RNase A from the beads, the dissociation constant and dissociation rate constant of the phage antibody from RNase A, and the time for blocking, equilibrium and washing in the biopanning process. A recommended biopanning protocol based on the model is also described.

Journal Article↗