Determinants of [ 13 N]ammonia kinetics in hepatic PET experiments: a minimal recirculatory model

Background The disposition of propofol in man is commonly described using a three-compartment mamillary model. However, these models do not incorporate blood flows as parameters. This complicates the representation of the changes in blood flows that may occur in surgical patients. In contrast, complex physiologically based models are derived from data sets (e.g., tissue:blood partition coefficients) that may not be readily collected in man. Methods Alternatively, the authors report a recirculatory model of propofol disposition in a "standard" man that incorporates detailed descriptions of the lungs and brain, but with a lumped description of the remainder of the body. The model was parameterized from data in the literature using a "meta-modeling" approach. The first-pass passage of propofol through the venous vasculature and the lungs was a function of the injected drug mixing with cardiac output and passing through a three-"tank in series" model for the lungs. The brain was represented as a two-compartment model defined by cerebral blood flow and a permeability term. The Bispectral Index was a linear function of the mean brain concentration. The remainder of the body was represented by compartment systems for the liver, fast distribution and slow distribution. Results The model was a good fit of the data and was able to predict other data not used in the development of the model. Conclusions The model may ultimately find a role in improving the fidelity of patient simulators currently used to train anesthetists and for clinical practice simulation to optimize dosing and management strategies.

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A Recirculatory Model for Pharmacokinetics and the Effects on Bispectral Index After Intravenous Infusion of the Sedative and Anesthetic AZD3043 in Healthy Volunteers

Anesthesia & Analgesia ◽

10.1213/ane.0000000000000814 ◽

2015 ◽

Vol 121 (4) ◽

pp. 904-913 ◽

Cited By ~ 8

Author(s):

Marcus A. Björnsson ◽

Åke Norberg ◽

Sigridur Kalman ◽

Ulrika S. H. Simonsson

Keyword(s):

Healthy Volunteers ◽

Bispectral Index ◽

Intravenous Infusion ◽

Recirculatory Model

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A recirculatory model for tissue plasminogen activator with saturable endothelial binding

British Journal of Clinical Pharmacology ◽

10.1046/j.1365-2125.2002.t01-13-01714.x ◽

2002 ◽

Vol 54 (5) ◽

pp. 558-558

Author(s):

M. J. B. KEMME ◽

R. C. SCHOEMAKER ◽

M. VD LINDEN ◽

C. KLUFT ◽

J. BURGGRAAF ◽

...

Keyword(s):

Plasminogen Activator ◽

Tissue Plasminogen Activator ◽

Tissue Plasminogen ◽

Recirculatory Model

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First-pass Lung Uptake and Pulmonary Clearance of Propofol

Anesthesiology ◽

10.1097/00000542-199912000-00032 ◽

1999 ◽

Vol 91 (6) ◽

pp. 1780-1780 ◽

Cited By ~ 43

Author(s):

Jette A. Kuipers ◽

Fred Boer ◽

Wim Olieman ◽

Anton G. L. Burm ◽

James G. Bovill

Keyword(s):

Pulmonary Tissue ◽

Tissue Compartment ◽

Arterial Blood ◽

Concentration Time ◽

Pulmonary Uptake ◽

First Pass ◽

Recirculatory Model ◽

Pass Through ◽

The Right ◽

Kinetics Of

Background The principal site for elimination of propofol is the liver. The clearance of propofol exceeds hepatic blood flow; therefore, extrahepatic clearance is thought to contribute to its elimination. This study examined the pulmonary kinetics of propofol using part of an indocyanine green (ICG) recirculatory model. Methods Ten sheep, immobilized in a hammock, received injections of propofol (4 mg/kg) and ICG (25 mg) via two semipermanent catheters in the right internal jugular vein. Arterial blood samples were obtained from the carotid artery. The ICG injection was given for measurement of intravascular recirculatory parameters and determination of differences in propofol and ICG concentration-time profiles. No other medication was given during the experiment, and the sheep were not intubated. The arterial concentration-time curves of ICG were analyzed with a recirculatory model. The pulmonary uptake and elimination of propofol was analyzed with the central part of that model extended with a pulmonary tissue compartment allowing elimination from that compartment. Results During the experiment, cardiac output was 3.90+/-0.72 l/min (mean +/- SD). The blood volume in heart and lungs, measured with ICG, was 0.66+/-0.07 l. A pulmonary tissue compartment of 0.47+/-0.16 l was found for propofol. The pulmonary first-pass elimination of propofol was 1.14+/-0.23 l/min. Thirty percent of the dose was eliminated during the first pass through the lungs. Conclusions Recirculatory modeling of ICG allows modeling of the first-pass pulmonary kinetics of propofol concurrently. Propofol undergoes extensive uptake and first-pass elimination in the lungs.

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Using Front-end Kinetics to Optimize Target-controlled Drug Infusions

Anesthesiology ◽

10.1097/00000542-200311000-00013 ◽

2003 ◽

Vol 99 (5) ◽

pp. 1078-1086 ◽

Cited By ~ 54

Author(s):

Michael J. Avram ◽

Tom C. Krejcie

Keyword(s):

Intravenous Administration ◽

Pharmacokinetic Model ◽

Sampling Site ◽

Model Parameters ◽

Drug Infusion ◽

Concentration Data ◽

Blood Concentrations ◽

Compartment Models ◽

Drug Concentrations ◽

Recirculatory Model

Background The mode of drug administration, blood sampling schedule, and sampling site affect the pharmacokinetic model derived. The present study tested the hypothesis that three-compartment pharmacokinetic model parameters derived from arterial drug concentrations obtained after rapid intravenous administration can be used to design a target-controlled drug infusion (TCI) that deviates minimally from the target. Methods Arterial thiopental concentration data obtained from the moment of injection in a previous study of five dogs were used. Three three-compartment models were constructed, one based on early concentrations classically obtained at 1, 2, and 3 min; another using all concentrations obtained beginning with the thiopental recirculation peak; and the last with the initial distribution volume (VC) fixed to the sum of VC and the nondistributive volume of the recirculatory model from the earlier study. Using these models, TCIs were designed that would maintain 20 mug/ml thiopental concentrations in VC for 60 min if simulated with the models used in their design. Drug concentrations resulting from these TCIs were then simulated using recirculatory model kinetics, and prediction errors were evaluated. Results Models with VCs estimated from intermittent or frequent early blood concentrations overestimated not only VC but also the volume and clearance of the rapidly equilibrating tissues, and their TCIs significantly overshot the target. With VC fixed to recirculatory model parameters, drug distribution was described in a manner consistent with that of the recirculatory model, and the TCI deviated minimally from the target. A similar three-compartment model was derived from data obtained from a simulation of a 2-min infusion using recirculatory kinetic parameters. Conclusions Because three-compartment models based on drug concentration histories obtained after rapid intravenous administration do not characterize VC accurately, TCIs based on them produce concentrations exceeding the target. A model capable of producing TCIs deviating minimally from the target can be derived from data obtained during and after a brief drug infusion.

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Recirculatory Pharmacokinetics and Pharmacodynamics of Rocuronium in Patients

Anesthesiology ◽

10.1097/00000542-200101000-00012 ◽

2001 ◽

Vol 94 (1) ◽

pp. 47-55 ◽

Cited By ~ 36

Author(s):

Jette A. Kuipers ◽

Fred Boer ◽

Erik Olofsen ◽

James G. Bovill ◽

Anton G. L. Burm

Keyword(s):

Cardiac Output ◽

Indocyanine Green ◽

Pharmacokinetic Model ◽

Good Description ◽

Mean Transit Time ◽

Maximum Effect ◽

Pharmacokinetics And Pharmacodynamics ◽

Fast Onset ◽

Recirculatory Model ◽

The Mean

Background Recirculatory models are capable of accurately describing first-pass pharmacokinetics and the influence of cardiac output (CO), which is important for drugs with a fast onset of effect. The influence of CO on pharmacokinetic and pharmacodynamic parameters of rocuronium in patients was evaluated using a recirculatory pharmacokinetic model. Methods Fifteen patients were included to study rocuronium pharmacokinetics and pharmacodynamics. Bolus doses of rocuronium (0.35 mg/kg) and indocyanine green (25 mg) were injected simultaneously via a peripheral intravenous catheter. Blood samples were taken for 240 min from the radial artery. The force of contraction of the adductor pollicis after a train-of-four at 2 Hz every 12 s was measured. Arterial concentration-time curves of rocuronium and indocyanine green were analyzed using a recirculatory model. Pharmacodynamics were described using a sigmoid maximum effect (Emax) model. Results The CO of the patients varied from 2.43 to 5.59 l/min. Total distribution volume of rocuronium was 17.3 +/- 4.8 l (mean +/- SD). The CO showed a correlation with the fast tissue clearance (Cl(T_f); r2 = 0.51), with the slow tissue clearance (Cl(T_s); r2 = 0.31) and with the mean transit times of rocuronium except for the mean transit time of the slow tissue compartment. The blood-effect site equilibration constant (k(e0)) was strongly correlated with CO (r2 = 0.70). Conclusions Cardiac output influences the pharmacokinetics, including k(e0), for rocuronium in patients. For drugs with a fast onset of effect, a recirculatory model, which includes CO, can give a good description of the relation between concentration and effect, in contrast to a conventional compartmental pharmacokinetic model.

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