Allopurinol kinetics in humans as a means to assess liver function: comparison of different models

1987 ◽  
Vol 253 (2) ◽  
pp. R352-R360 ◽  
Author(s):  
G. van Waeg ◽  
T. Groth ◽  
F. Niklasson ◽  
C. H. de Verdier
Keyword(s):  
Liver Function ◽  
Intravenous Injection ◽  
Healthy Subjects ◽  
Tight Binding ◽  
Compartment Model ◽  
Central Compartment ◽  
Fractional Rate ◽  
Computer Based ◽  
Loading Tests ◽  
Three Compartment Model

To describe the mechanisms involved in allopurinol kinetics after intravenous injection in humans, a number of alternative computer-based biodynamic models were designed. Distribution processes were described with two-compartment as well as with three-compartment kinetics for both allopurinol and its metabolite oxipurinol. These two major physiological alternatives were combined with biochemical models assuming either competitive or tight-binding-complex inhibition kinetics. The four resulting basic models were evaluated (and successively improved) using sets of plasma allopurinol and oxipurinol concentration curves, measured after intravenous injection in healthy subjects and in patients with different degrees of liver function. A three-compartment model with tight-binding-complex inhibition was selected and used to analyze the 35 loading tests performed. One of the parameters estimated in this way, the fractional rate constant for transport of allopurinol from the central compartment to the metabolically active (liver) compartment (kA31), turned out to be a powerful discriminative parameter between a group of healthy subjects, a group of patients with slightly to moderately reduced overall liver function, and a group with severely reduced overall liver function [kA31(min-1) = 0.136 +/- 0.042 (mean +/- SD, n = 13), 0.072 +/- 0.024 (n = 13), and 0.025 +/- 0.015 (n = 8), respectively].

Population Pharmacokinetics of Propofol

2000 ◽  
Vol 92 (3) ◽  
pp. 727-738 ◽  
Author(s):  
Jürgen Schüttler ◽  
Harald Ihmsen
Keyword(s):  
San Francisco ◽  
Sampling Site ◽  
Compartment Model ◽  
Central Compartment ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Power Functions ◽  
Target Controlled Infusion ◽  
Three Compartment Model ◽  
Elimination Clearance

Background Target-controlled infusion is an increasingly common type of administration for propofol. This method requires accurate knowledge of pharmacokinetics, including the effects of age and weight. The authors performed a multicenter population analysis to quantitate the effects of covariates. Methods The authors analyzed 4,112 samples of 270 individuals (150 men, 120 women, aged 2-88 yr, weighing 12-100 kg). Population pharmacokinetic modeling was performed using NONMEM (NONMEM Project Group, University of California, San Francisco, CA). Inter- and intraindividual variability was estimated for clearances and volumes. The effects of age, weight, type of administration and sampling site were investigated. Results The pharmacokinetics of propofol were best described by a three-compartment model. Weight was found to be a significant covariate for elimination clearance, the two intercompartmental clearances, and the volumes of the central compartment, the shallow peripheral compartment, and the deep peripheral compartment; power functions with exponents smaller than 1 yielded the best results. The estimates of these parameters for a 70-kg adult were 1.44 l/min, 2.25 l/min, 0.92 l/min, 9.3 l, 44.2 l, and 266 l, respectively. For patients older than 60 yr the elimination clearance decreased linearly. The volume of the central compartment decreased with age. For children, all parameters were increased when normalized to body weight. Venous data showed a decreased elimination clearance; bolus data were characterized by increases in the volumes of the central and shallow peripheral compartments and in the rapid distribution clearance (Cl2) and a decrease in the slow distribution clearance (Cl3). Conclusions Pharmacokinetics of propofol can be well described by a three-compartment model. Inclusion of age and weight as covariates significantly improved the model. Adjusting pharmacokinetics to the individual patient should improve the precision of target-controlled infusion and may help to broaden the field of application for target-controlled infusion systems.

Bicarbonate kinetics in humans: identification and validation of a three-compartment model

1995 ◽  
Vol 269 (1) ◽  
pp. E183-E192 ◽  
Author(s):  
M. P. Saccomani ◽  
R. C. Bonadonna ◽  
E. Caveggion ◽  
R. A. DeFronzo ◽  
C. Cobelli
Keyword(s):  
Specific Activity ◽  
Model Identification ◽  
Compartment Model ◽  
Central Compartment ◽  
Good Evidence ◽  
The Body ◽  
Endogenous Production ◽  
Three Compartment Model ◽  
Expired Air

A model of bicarbonate kinetics is crucial to a correct interpretation of experiments for measuring oxidation in vivo of carbon-labeled compounds. The aim of this study is to develop a compartmental model of bicarbonate kinetics in humans from tracer data by devoting particular attention to model identification and validation. The data base consisted of impulse-dose studies of 14C-labeled bicarbonate in nine normal subjects. The decay curve of specific activity of CO2 in expired air (saRCO2) was frequently sampled for 4-7 h. In addition, endogenous production of CO2, VCO2, was measured by indirect calorimetry. A model of data, i.e., an exponential model, analysis of decay curves of saRCO2 showed first that three compartments are necessary and sufficient to describe bicarbonate tracer kinetics. Compartmental models were then used as models of system. To correctly describe the input-output configuration, labeled CO2 flux in the expired air, phi RCO2 (= saRCO2.VCO2), has been used as measurement variable in tracer model identification. A mammillary three-compartment model with a respiratory and a nonrespiratory loss has been studied. Whereas there is good evidence that respiratory loss takes place in the central compartment, whether nonrespiratory loss is taking place in the central compartment or in one of the two peripheral compartments is uncertain. Thus three competing tracer models were considered. Using a model-independent analysis of data, based on the body activity variable, to calculate mean residence time in the system, we have been able to validate a specific model structure, i.e., with the two irreversible losses taking place in the central compartment. This validated tracer model was then used to quantitate bicarbonate masses in the system. Because there is uncertainty about where endogenous production enters the system, lower and upper bounds of masses of bicarbonate in the body are derived.

Population pharmacokinetics (PPK) of eribulin mesylate in patients with locally advanced or metastatic breast cancer (MBC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2524-2524 ◽  
Author(s):  
M. Jansen ◽  
M. Vernaz-Gris ◽  
C. DesJardins ◽  
N. Wong ◽  
M. Campone ◽  
...  
Keyword(s):  
Renal Function ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Compartment Model ◽  
Central Compartment ◽  
Volume Of Distribution ◽  
Eribulin Mesylate ◽  
Minor Fraction ◽  
Three Compartment Model ◽  
A Minor

2524 Background: Eribulin mesylate (E7389) is a non-taxane microtubule dynamics inhibitor with a novel mechanism of action. A study was conducted to evaluate efficacy, safety and pharmacokinetics of eribulin at a dose of 1.4 mg/m2 for locally advanced or MBC in patients previously treated with an anthracycline, a taxane, and capecitabine. Methods: Eribulin was administered intravenously over 2–5 minutes at a dose of 1.4 mg/m2 on days 1 and 8 of a 21- day cycle to 291 patients. Four plasma samples were collected between 5 min and 120 hours after the first dose. Plasma eribulin concentrations were determined by LC/MS/MS. A total of 774 samples, from 209 patients with complete dose and sampling information were included in the PPK analysis, which was conducted using nonlinear mixed effects modeling (NONMEM). Results: Eribulin PKs were best described by a three-compartment model, with elimination from the central compartment. Distribution was rapid and elimination slow. For a typical patient with AST<ULN and CLCR=101mL/min (Cockroft-Gault), clearance (CL) was 2.98 L/h and central volume of distribution 3.72 L (V1). Volumes and inter-compartmental clearances for the two peripheral compartments were 3.60 L (V2), 126 L (V3), 2.7 L/h (Q2) and 5.6 L/h (Q3). Inter-patient variability on CL was 57%, and ranged from 26- 98% for other parameters. Residual error was 21% (proportional). CL was on average 38% lower in patients with AST>ULN and positively correlated with renal function. The covariate effects only explained a minor fraction of inter-patient variability in this single study dataset. Conclusions: Eribulin PKs were described by a three-compartment model with rapid distribution and slow elimination. Appreciable interpatient PK variability exists, a minor fraction of which was explained by measures of liver and renal function. [Table: see text]

Vertebral fractures and luxations in dogs and cats part 2: treatment and surgery options

2021 ◽  
Vol 26 (3) ◽  
pp. 15-19
Author(s):  
Ivona Orgonikova ◽  
Josep Brocal ◽  
Giunio Bruto Cherubini ◽  
Viktor Palus
Keyword(s):  
Spinal Cord ◽  
Vertebral Fractures ◽  
Vertebral Column ◽  
Compartment Model ◽  
Spinal Instability ◽  
Decompression Surgery ◽  
Implant Loosening ◽  
Bone Fragment ◽  
Three Compartment Model ◽  
Disc Extrusion

Assessing the presence of vertebral column instability is essential in animals with vertebral fractures or luxations. Spinal instability is most commonly assessed using a three-compartment model and unstable vertebral fractures and luxations require surgical stabilisation. In cases of compression of the spinal cord (by haematoma, traumatic intervertebral disc extrusion or bone fragment), decompression surgery is necessary. Prompt surgery prevents additional spinal cord damage, but the overall condition of the patient, including any concurrent injuries, needs to be continually kept in mind. The vertebral column can be stabilised using multiple techniques, such as screws, pins, polymethylmetacrylate and plating techniques, as well as external stabilisation and spinal stapling. Complications of spinal surgeries include haemorrhage, infection, neurological deterioration, particularly in cases of spinal stabilisations, implant loosening and failure.

Pharmacokinetics and Tissue Residues of Sulfathiazole and Sulfamethazine in Pigs

1994 ◽  
Vol 57 (9) ◽  
pp. 796-801 ◽  
Author(s):  
LIEVE S. G. VAN POUCKE ◽  
CARLOS H. VAN PETEGHEM
Keyword(s):  
Intravenous Injection ◽  
Half Life ◽  
Intramuscular Injection ◽  
Compartment Model ◽  
Absolute Bioavailability ◽  
Pharmacokinetic Parameters ◽  
Tissue Concentrations ◽  
Single Intravenous Injection ◽  
The Individual ◽  
Residue Study

The plasma pharmacokinetics and tissue penetration of sulfathiazole (ST) and sulfamethazine (SM) after intravenous and intramuscular injection in pigs were studied. Following a single intravenous dose of 40 mg ST/kg of bodyweight or 80 mg SM/kg of bodyweight, the plasma ST and SM concentrations were best fitted to a two-compartment model. The areas under the curve were 447 ± 39 and 1485 ± 41 mg/h/L, clearances were 0.090 ± 0.007 and 0.054 ± 0.001 L/kg/h, volumes of distribution were 1.16 ± 0.16 and 0.77 ± 0.06 L/kg, half-lifes in distribution phase were l.18 ± 0.57 and 0.23 ± 0.16 h and half-lifes in eliminations phase were 9.0 ± l.6 and 9.8 ± 0.6 h. When the two compounds were administered simultaneously as a single intravenous injection, the pharmacokinetic parameters for ST were not significantly different. The values for SM show statistical differences for some important parameters: α, β and the AUC0–&gt;∞ were significantly decreased and t1/2α, Vd and CIB were significantly increased. It can be concluded that after a single intravenous injection of 40 mg/kg, sulfathiazole has a high tl/2β resulting in higher tissue concentrations. This half-life, which is higher than what is reported in the literature, is not influenced by the simultaneous presence of sulfamethazine. The tl/2β for sulfamethazine after a single intravenous injection of 80 mg/kg is comparable to the data from the literature and is not influenced by the presence of sulfathiazole. Sulfathiazole and SM were also administered simultaneously as an intramuscular injection to healthy pigs at a dosage of 40 and 80 mg/kg bodyweight. Pharmacokinetic experiments were conducted on three pigs. From this pharmacokinetic study it can be concluded that upon a single intramuscular administration of 40 mg/kg of ST and 80 mg/kg of SM the absolute bioavailability in pigs is 0.92 ± 0.04 for ST and l.01 ± 0.07 for SM. Six pigs received five intramuscular im) injections as a single dose of ST and SM every 24 h for five consecutive days for the residue study. The pigs were slaughtered at different times after the last dose was given and samples were taken from various tissues and organs. Concentrations were determined by a microbiological method and a HPTLC method. No edible tissue contained more than 100 μg/kg of the individual sulfonamides after 10 days of withdrawal. It means that adult animals which have a shorter half-life and thus lower tissue concentrations will certainly meet the economic community EC) maximum residue limits after a 10 days withdrawal period.

Disposition Kinetics of Disopyramide in Human Healthy Volunteers Described by an Open Three Compartment Model

1989 ◽  
Vol 64 (5) ◽  
pp. 412-416 ◽  
Author(s):  
Jan Bonde ◽  
Niels Melchior Jensen ◽  
Lars E. Pedersen ◽  
Helle R. Angelo ◽  
Seren N. Rasmussen ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Compartment Model ◽  
Disposition Kinetics ◽  
Three Compartment Model ◽  
Kinetics Of

scholarly journals Purified radiolabeled antithrombin III metabolism in three families with hereditary AT III deficiency: application of a three-compartment model

Blood ◽  
1986 ◽  
Vol 67 (1) ◽  
pp. 93-98
Author(s):  
EA Knot ◽  
E de Jong ◽  
JW ten Cate ◽  
AH Iburg ◽  
CP Henny ◽  
...  
Keyword(s):  
Antithrombin Iii ◽  
Polyacrylamide Gel Electrophoresis ◽  
Sodium Dodecyl ◽  
Compartment Model ◽  
Control Group ◽  
Surface Binding ◽  
Catabolic Rate ◽  
At Iii ◽  
Three Compartment Model ◽  
The Mean

Purified human radioiodinated antithrombin III (125I-AT III) was used to study its metabolism in six members from three different families with a known hereditary AT III deficiency. Six healthy volunteers served as a control group. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and crossed immunoelectrophoresis (CIE) showed the purified AT III to be homogeneous. Amino acid analysis of the protein revealed a composition identical to a highly purified internal standard. The specific activity was 5.6 U/mg. Analysis of plasma radioactivity data was performed, using a three-compartment model. Neither plasma disappearance half-times nor fractional catabolic rate constants differed significantly between patients and control subjects. The mean absolute catabolic rate in the patient group was significantly lower than that of the control group at 2.57 +/- 0.44 and 4.46 +/- 0.80 mg/kg/day, respectively. In addition, the mean patient alpha 1-phase, flux ratio (k1,2 and k2,1) of the second compartment alpha 2-phase and influx (k3,1) of the third compartment were significantly reduced as compared with control values. It has been tentatively concluded that the observed reduction in the second compartment may be caused by a decrease in endothelial cell surface binding.

scholarly journals The Concentration of Digoxin Activity after Intravenous in Three Compartments Mathematical Model

2019 ◽  
Vol 8 (2S11) ◽  
pp. 3653-3657
Keyword(s):  
Mathematical Model ◽  
Laplace Transform ◽  
Digoxin Concentration ◽  
Compartment Model ◽  
System Of Equations ◽  
Transfer Coefficients ◽  
Linear Ordinary Differential Equations ◽  
Concentration Time ◽  
The Laplace Transform ◽  
Three Compartment Model

Present paper is designed to compare the distribution of digoxin in three compartment model administered through an intravenous (i.v). These models under consideration is denoted by a system of non-linear ordinary differential equations. The Eigenvalue and the Laplace transform methods were used to solve the system of equations. Digoxin was administered to five subjects through Intravenous then, the serum digoxin concentrations were measured respectively over a period of 72 hours. The transfer coefficients were obtained from observed digoxin concentrations using method of residuals and the variation of digoxin concentration – time curves plotted using MATLAB.

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