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At least 325 records · Page 18Linked to original sources
PubMed1993

Effect of phenobarbital and p-hydroxyphenobarbital glucuronide on acetaminophen metabolites in isolated rat hepatocytes: use of a kinetic model to examine the rates of formation and egress.

Conventional analysis of initial uptake and egress rates in isolated hepatocytes is limited in the ability to distinguish between rates of metabolite formation and egress, and to separate basolateral and canalicular transport processes. The present study examined the applicability of kinetic modeling in describing acetaminophen glucuronide (AG) and acetaminophen sulfate (AS) formation and egress in hepatocytes after acute exposure to phenobarbital or p-hydroxyphenobarbital glucuronide (p-OHPBG) in vitro, or in vivo phenobarbital pretreatment. A significant pretreatment effect on AG and AS disposition was seen based on initial rates of egress. In vivo phenobarbital pretreatment decreased the initial egress rate of AG compared to vehicle pretreatment, and the initial egress rate of AS compared to all other treatments. A pharmacokinetic model incorporating AG and AS formation in hepatocytes as well as egress processes (including diffusional and active transport components) was fit to the data. Parameter estimates derived from model fits to the data showed the expected increase in acetaminophen glucuronidation and decrease in sulfation after phenobarbital pretreatment; in addition, an increase in the AG diffusional rate constant and a decrease in the AS diffusional rate constant was apparent. The excretion Vmax for AG was decreased statistically after acute phenobarbital exposure in vitro, and in vivo phenobarbital pretreatment, with a concomitant statistical increase in the Km for AG excretion. In vitro acute p-OHPBG exposure also decreased significantly the excretion Vmax for AG. These data are consistent with the hypothesis that phenobarbital-impaired biliary excretion of AG is a function of impaired canalicular transport due to the presence of p-OHPBG. They further suggest that the mechanism may not be simple competitive inhibition. This work demonstrates the utility of a kinetic modeling approach to differentiate metabolic and transport processes when analyzing data from isolated hepatocyte studies. Additional information may be gained that would not be apparent by conventional methods of analysis.

Acetaminophen↗
PubMed1997

Consequences of using a simplified kinetic model for dynamic PET data.

UNLABELLED: We compared a physiological model of 82Rb kinetics in the myocardium with two reduced-order models to determine their usefulness in assessing physiological parameters from dynamic PET data. METHODS: A three-compartment model of 82Rb in the myocardium was used to simulate kinetic PET ROI data. Simulations were generated for eight different blood-flow rates reflecting the physiological range of interest. Two reduced-order models commonly used with myocardial PET studies were fit to the simulated data, and parameters of the reduced-order models were compared with the physiological parameters. Then all three models were fit to the simulated data with noise added. Monte Carlo simulations were used to evaluate and compare the diagnostic utility of the reduced-order models. A description length criterion was used to assess goodness of fit for each model. Finally, fits to simulated data were compared with fits to actual dynamic PET data. RESULTS: Fits of the reduced-order models to the three-compartment model noise-free simulated data produced model misspecification artifacts, such as flow parameter bias and systematic variation with flow in estimates of nonflow parameters. Monte Carlo simulations showed some of the parameter estimates for the two-compartment model to be highly variable at PET noise levels. Fits to actual PET data showed similar variability. One-compartment model estimates of the flow parameter at high and low flow were separated by several s.d.s for both the simulated and the real data. With the two-compartment model, the separation was about one s.d., making it difficult to differentiate a high and a low flow in a single experiment. Fixing nonflow parameters reduced flow parameter variability in the two-compartment model and did not significantly affect variability in the one-compartment model. Goodness of fit indicated that, at realistic noise levels, both reduced-order models fit the simulated data at least as well as the three-compartment model that generated the data. CONCLUSION: The one-compartment reduced-order model of 82Rb dynamic PET data can be used effectively to compare myocardial blood-flow rates at rest and stress levels. The two-compartment model can differentiate flow only if a priori values are used for nonflow parameters.

Animals↗
PubMed2004

Kinetic model of imidazologlycerol-phosphate synthetase from Escherichia coli.

Based on the available experimental data, we developed a kinetic model of the catalytic cycle of imidazologlycerol-phosphate synthetase from Escherichia coli accounting for the synthetase and glutaminase activities of the enzyme. The rate equations describing synthetase and glutaminase activities of imidazologlycerol-phosphate synthetase were derived from this catalytic cycle. Using the literature data, we evaluated all kinetic parameters of the rate equations characterizing individually synthetase and glutaminase activities as well as the contribution of each activity depending on concentration of the substrates, products, and effectors. As shown, in the presence of 5 -phosphoribosylformimino-5-aminoimidazolo-4-carboxamideribonucleotide (ProFAR) and imidazologlycerol phosphate (IGP) glutaminase activity dominates over synthetase activity at sufficiently low concentrations of 5 -phosphoribulosylformimino-5-aminoimidazolo-4-carboxamideribonucleotide (PRFAR). Increased PRFAR concentrations resulted in decreased contribution of glutaminase activity and, consequently, increased the contribution of synthetase activity in the enzyme functioning.

Aminohydrolases↗
PubMed1994

Urea kinetic modeling: an in vitro and in vivo comparative study.

The urea kinetic model (UK) and the direct dialysis quantification method based on dialysate collection (DDQ) were used to determine the urea distribution volume (V) identified with the total body water and the urea generation rate (G) for different dialysis times, both in vivo during short hemodialysis (N = 20) and in vitro using an experimental single-pool urea system (N = 10). Both UK and DDQ allowed a satisfactory in vitro estimation of V and G for all dialysis times. On the other hand in vivo V and G estimations by both methods showed an increase of more than 50% between the determinations performed after 30 minutes of dialysis and at the end of dialysis. Our theoretical analysis shows that the in vivo changes of V are compatible with those expected for a two-compartment system in which one compartment is cleared faster than the other. Furthermore, given that urea is allowed to equilibrate in the body at the end of dialysis, DDQ permits an accurate estimate of V, G and PCR even for short hemodialysis, which UK does not.

Dialysis Solutions↗
PubMed2005

Small-bowel perfusion measurement: feasibility with single-compartment kinetic model applied to dynamic contrast-enhanced CT.

This study was institutional review board approved and HIPAA compliant. Informed consent was obtained from all patients. The purpose of the study was to prospectively examine the feasibility of measuring small-bowel quantitative blood flow by using motion-corrected, contrast-enhanced computed tomographic (CT) images and a single-compartment kinetic model. Seven patients underwent abdominal CT in which 40 10-mm-thick sections were obtained at a single level. Small-bowel images were obtained every 3 seconds after contrast agent administration. Automated application of regions of interest yielded time-enhancement curves for the bowel wall and the aorta. A one-compartment model was applied to each set of time-enhancement curves for determination of the small-bowel volumetric blood flow F(V), volume of distribution V(D), and blood transit time tau. F(V) was also calculated by using the first-pass method and gamma variate analysis for model validation. The F(V) values obtained by using the single-compartment model (mean F(V), 0.47 min(-1)) showed excellent linear correlation with those obtained by using the first-pass method (Pearson r = 0.80) and gamma variate analysis (Pearson r = 0.97). Mean V(D) and tau values were 2.86 (unitless) and 4.28 seconds, respectively. A one-compartment kinetic model can be applied to motion-corrected, contrast-enhanced small-bowel CT images to quantify perfusion.

Blood Flow Velocity↗
PubMedDate not supplied

A kinetic model for predicting the release rate of sparingly-water-soluble drugs from a hydrogel-coated polymeric matrix.

Medical devices used for on-target drug delivery are often coated with a hydrogel coating for friction-reduction purpose. Thus, the delivery of a sparingly-water-soluble drug by such a device must diffuse through a nonerodable hydrogel layer. An empirical rate equation has been derived for such a kinetic model and predicts that the rate of drug release from such a device is directly proportional to the loading of the drug in the polymeric matrix. The validity of this kinetic model was examined by measuring the rate of release of 2,4,4'-trichloro-2'-hydroxydiphenyl ether from different hydrogel-coated (ethylene-vinyl acetate) copolymer stents containing a wide range of the drug. The experimentally determined release rates are in reasonably good agreement with those calculated from the empirical rate equation. Bioefficacy test results based on zone-of-inhibition test against Escherichia coli are also in good agreement with the release rate and drug-loading data predicted according to the empirical rate equation.

Forecasting↗
PubMed1990

The role of urea kinetic modeling, TACurea, and Kt/V in achieving optimal dialysis: a critical reappraisal.

The National Cooperative Dialysis Study (NCDS) established the importance of the time-averaged concentration of blood urea nitrogen (BUN) (TACurea) as a determinant of morbidity among patients maintained on hemodialysis. Although urea is not itself toxic, it serves as a surrogate for those low-molecular weight products of protein catabolism that do contribute to uremic toxicity. The NCDS also reported an association between low protein catabolic rates (a measure of dietary protein intake) and increased morbidity, but the validity of this result has been questioned. On the basis of a retrospective re-analysis of the data, Gotch and Sargent have proposed following the normalized whole-body urea clearance, Kt/V, as a more fundamental index of the level of dialytic therapy. In this review, a comparison is made between these two measures of adequate dialysis, namely, midweek predialysis urea concentration and Kt/V. At least for the cellulosic membranes used in the NCDS, they seem to be equivalent. Furthermore, each prescription defines adequate nutrition as a dietary protein intake (DPI) of 1.0 g/kg/d. At this DPI, a time-averaged concentration of BUN of 17.9 mmol/L (50 mg/dL) (corresponding roughly to a midweek predialysis BUN of 21.4 to 28.6 mmol/L (60 to 80 mg/dL), as recommended by the NCDS, is equivalent to a Kt/V of 1.0, as recommended by Gotch and Sargent. Based on ease and accuracy of measurement, TACurea would seem the more reliable marker for monitoring the adequacy of dialysis. Extrapolation of the utility of TACurea and/or Kt/V to noncellulosic membranes remains to be established. Urea kinetic modeling constitutes a powerful mathematical tool for implementing these recommendations. Urea kinetic modeling may also be used as a means of monitoring DPI and thereby ensuring adequate nutrition.

Blood Urea Nitrogen↗
PubMed2002

A kinetic model describing cell growth and production of highly active, recombinant ice nucleation protein in Escherichia coli.

A structured kinetic model, which describes the production of the recombinant ice nucleation protein in different conditions, was applied. The model parameters were estimated based on the variation of the specific growth rate and the intracellular product concentration during cultivation. The equations employed relate the cellular plasmid content or plasmid copy number with the cloned-gene expression; these correlations were successfully tested on the experimental data. The optimal nutrient conditions for the growth of Escherichia coli expressing the inaZ gene of Pseudomonas syringae were determined for the production of active ice nucleation protein. The kinetics of the cultures expressing the inaZ gene were studied in a bioreactor at different growth temperatures and nutrient conditions.

Bacterial Outer Membrane Proteins↗
PubMed2002

Kinetic model for Fe(II) oxidation in seawater in the absence and presence of natural organic matter.

A detailed kinetic model has been developed to describe the oxidation of Fe(II) in seawater in both the absence and the presence of natural organic material. Experimental data were collected using a luminol chemiluminescence-based method to measure Fe(II), assuming that both the inorganic and the organically complexed species were detected. In the absence of organic matter, the data were modeled based on the Haber-Weiss mechanism with the inclusion of a back-reaction of Fe(III) with superoxide and precipitation of Fe(OH)3. Both reactions were found to be significant using sensitivity analysis. When organic matter is present, the model was extended by organic complexation of Fe(II) and Fe(III) with the creation of a parallel oxidation pathway for Fe(II). Fe(II) oxidation at natural (nanomolar) concentrations was accurately predicted for a range of organic concentrations. The model also accounted for scavenging of superoxide by sub-nanomolar levels of dissolved copper and by organic matter when present. The presence of a relatively strong Fe(III) binding ligand was observed to significantly increase the rate of Fe(II) oxidation, while ultimately retaining most of the iron in the system in dissolved (organically complexed) form. The complexation reactions and reaction of inorganic and organically bound Fe(II) with oxygen were found to be critical reactions in the system, while Fe(III) hydrolysis became unimportant even at low organic concentrations. The superoxide radical was also observed to have a major role in the cycling of iron due to its ability to act as both an oxidant and a reductant. The model indicates that the rate constant for the reaction of Fe(II) with O2 has generally been underestimated in previous work and that the secondary oxidation of Fe(II) by H2O2 and subsequently OH* plays a relatively minor role in these systems.

Hydroxyl Radical↗
PubMed2003

A structured kinetic model for suspension cultures of Taxus chinensis var. mairei induced by an oligosaccharide from Fusarium oxysporum.

A structured kinetic model was established to describe the process of Taxol formation in suspension cultures of Taxus chinesis var. mairei induced by an oligosaccharide from Fusarium oxysporum. In this model, the role of intracellular starch as a storage carbon source had to be taken into account. Substrate uptake, culture growth, cell respiration, and secondary metabolites, predicted by the model, agreed with those obtained experimentally. The effective factors of oligosaccharide elicitation, eta(e,j), defined as the ratio of the parameter values in the system with oligosaccharide to those in control, reflected the effects of the oligosaccharide on cell growth and Taxol production.

Bioreactors↗
PubMed2004

Probabilistic kinetic model of slow oxidation of low-density lipoprotein: II. Experiments.

Theoretical probabilistic kinetic model has been applied to describe the measurements of several oxidation markers as a function of time, during slow oxidation of low-density lipoprotein (LDL). It has been demonstrated that such a process could be described as tocopherol-mediated peroxidation (TMP), initiated and sustained by the action of copper ions, present in LDL in trace amounts. In that process concentration of alpha-tocopherol remains essentially unaltered. Tocopherol and copper ions act as catalysts, oscillating between the oxidized and reduced states. The fitting of the theoretical model to the experimental data resulted in determination of the numerical values for the kinetic parameters. It has been found that the parameter values used for the fitting of the data collected for a number of samples from various donors differ rather little. The kinetic chain length of 1.3 (in presence of co-antioxidants) and 2.9 (in the absence of co-antioxidants) is shorter than found by others. The difference probably comes from the much lower concentration of copper ions in our systems (about 0.1 ion per LDL particle).

Copper↗
PubMed1987

A kinetic model for lipoxygenases based on experimental data with the lipoxygenase of reticulocytes.

A comprehensive kinetic model for lipoxygenase catalysis is proposed which includes the simultaneous occurrence of dioxygenase and hydroperoxidase activities and is based on the assumption of a single binding site for substrate fatty acid and product. The aerobic reaction of purified lipoxygenase from rabbit reticulocytes with 9,12(Z,Z)-octadecadienoic acid (linoleic acid) as substrate was studied. The rate constants and the dissociation constants of this enzyme were calculated for the model from progress curves; the model describes correctly the experimental data. The following kinetic features of the reticulocyte enzyme are assumed to apply generally to lipoxygenases. (a) The enzyme shows autoactivation by its product. (b) The rate-limiting step is the hydrogen abstraction. (c) Both substrate fatty acid and its product are competitive inhibitors of the lipoxygenase. (d) Lowering the oxygen concentration enhances the degree of substrate inhibition, whereas product inhibition is not influenced. (e) If substrate is in excess the oxygen concentration determines the share of dioxygenase and hydroperoxidase activities of the enzyme. As predicted from the model it was found that at low concentrations of oxygen the regio- and stereo-specificities of the dioxygenation are diminished. During the autoactivation phase the steady-state approximation does not hold.

Animals↗
PubMedDate not supplied

Application of a kinetic model on the methionine accumulation in intracranial tumours studied with positron emission tomography.

Eleven patients were studied with positron emission tomography (PET) using 11C-methionine. They all had low-grade astrocytomas (Kernohan grade II). The PET studies were analyzed with a metabolic model to obtain values for the influx, the accumulation rate and the partition coefficient of methionine in normal and tumourous tissue. Seven of the tumours showed an increased accumulation of methionine as compared with normal tissue on the static PET scans and also had higher values as to the kinetic parameters. Four tumours had a methionine accumulation equal to or lower than that of normal tissue and the kinetic parameters were also lower. Application of the kinetic model did not aid significantly in the delineation of the tumours. There was a correlation between the three parameters indicating an adaptation of the transport of methionine to the regional metabolic demand. The accumulation rate for normal cortical tissue was 0.49 nmol/g/min, the influx 0.97 nmol/ml and the partition coefficient 0.45 ml/g. These values are considerably higher than those previously reported. The differences might be attributed to differences in the corrections introduced for i.a. the occurrence of labelled metabolites in serum. With the use of a kinetic model, more information about the tracer is utilized and gained compared with the previously used graphic approach.

Brain Neoplasms↗
PubMed1993

Kinetic models of laser-tissue fusion processes.

Laser tissue fusion processes depend primarily on thermal denaturization of tissue collagen: the fibrils of apposed collagen strands apparently unravel under sufficient heat and re-entwine during the cooling phase. Excessive heating desiccates the fibers to a brittle state unsuitable for fusion while inadequate heating results in weak bonds. In all cases local heat transfer processes significantly affect, and may dominate, the thermal damage realized. Consequently, in addition to spot size power and beam activation time, the choice of laser wavelength is critically dependent on the particular vessel or tissue geometry (chiefly the thickness). We have conducted parametric studies on tissue welding laser activation protocols in transient finite difference numerical models which include tissue water vaporization processes in parallel with kinetic models of collagen and smooth muscle thermal damage. The results show the complex inter-relationship between laser parameters and tissue geometry which determines whether successful fusion may be obtained. The advantage of the numerical modeling approach is that individual physical processes may be studied singly to determine their relative importance.

Animals↗
PubMed1993

Kinetic model of water and urea permeability regulation by vasopressin in collecting duct.

We present a mathematical model describing the kinetics of water-channel and urea-carrier regulation by vasopressin in the apical membrane of collecting duct cells. The rate of change of the number of activated channels or carriers in the apical membrane is modeled as a balance between the rate of activation (or exocytic insertion) and the rate of inactivation (or endocytic retrieval) of transporters. In a three-state version of the model, transporters are assumed to be partitioned into three physical states, i.e., an "activated" state that imparts a permeation pathway to the apical membrane, an "inactivated" state, and a "reserve" state. Both activation and inactivation are represented by first-order kinetic equations describing transition from reserve to activated transporters and from activated to inactivated transporters, respectively. A simplified two-state model is derived from the three-state model, with the assumption that the transformation from inactivated to reserve transporter occurs rapidly relative to the other state transitions. Simulated time courses obtained by solving model equations are compared with experimentally determined time courses to test whether the response to vasopressin in isolated inner medullary collecting duct segments can be explained by direct effects on the rate constants for activation or inactivation. The results indicate that, for both transporters, it must be assumed that vasopressin directly regulates rate constants for both activation (exocytosis) and inactivation (endocytosis) to account for the experimentally determined dynamic responses to vasopressin and its withdrawal. These studies provide a theoretical basis on which to design further experimental studies.

Animals↗
PubMed1997

Comparison between urea removal in hemodialysis and continuous ambulatory peritoneal dialysis using a mathematical kinetic model.

Urea removal by continuous ambulatory peritoneal dialysis (CAPD) was compared with that by hemodialysis (HD) using a mathematical kinetic model. The time-averaged urea-nitrogen concentration (TAC) in the blood of a patient on maintenance HD was calculated by the model. Clearance with HD giving a TAC value equal to the constant urea-nitrogen concentration in the blood of a patient on CAPD was obtained, leading to the relation of equivalent clearances between HD and CAPD on the assumption that the urea-generation rate of the patient on CAPD was equal to that of the patient on HD.

Blood Urea Nitrogen↗
PubMed1979

A kinetic model of protein synthesis. Application to hemoglobin synthesis and translational control.

We present a kinetic model of protein synthesis which encompasses initiation, elongation, and termination parameters. We have investigated the dependence of the total rate of protein synthesis and the size of the translating polysomes on each of these parameters and in particular on the level of active 40 S ribosomes and initiation factors. This model qualitatively fits experimental data for the ratio of alpha- to beta-globin synthesis in reticulocytes, both under normal conditions and in the presence of inhibitors of chain initiation. This model has also been used to examine the effect that limiting amounts of certain tRNAs might have on the total rate of protein synthesis. In addition, the role of initiation factor discrimination and mRNA length are examined with respect to the differential translation of mRNAs.

Animals↗