First-pass Lung Uptake and Pulmonary Clearance of Propofol 

1999 ◽  
Vol 91 (6) ◽  
pp. 1780-1780 ◽  
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.

The Pulmonary First-pass Uptake of Five Nondepolarizing Muscle Relaxants in the Pig 

1999 ◽  
Vol 90 (2) ◽  
pp. 477-483 ◽  
Author(s):  
Ton M. Beaufort ◽  
Johannes H. Proost ◽  
Martin C. Houwertjes ◽  
Jan Roggeveld ◽  
Mark J.K. H. Wierda
Keyword(s):  
Mean Transit Time ◽  
Onset Time ◽  
Muscle Relaxants ◽  
Arterial Blood ◽  
Tibialis Muscle ◽  
Pulmonary Uptake ◽  
Org 9487 ◽  
First Pass ◽  
The Right ◽  
Org 7617

Background It is not known whether the lungs influence the early pharmacokinetics of muscle relaxants and, if they do, whether differences in pulmonary uptake contribute to the differences in potency and/or onset time among muscle relaxants. Because the lungs are uniquely positioned, receive the entire cardiac output, have a large capillary surface area, and can temporarily store various basic drugs, the authors determined whether substantial pulmonary first-pass uptake of muscle relaxants occurs. Methods In 14 pigs, rocuronium, vecuronium, Org 9487, Org 7617, or d-tubocurarine were administered simultaneously with indocyanin green within 1 s into the right ventricle, and then arterial blood was sampled every 1.2 s (in the first min). The tibialis muscle response was registered mechanomyographically. Results The maximum block was 93% (68-100% [median and range]). Onset times ranged from 83 s (78-86 s) for rocuronium to 182 s (172-192 s) for d-tubocurarine. Fraction-versus-time outflow curves showed that the peak of muscle relaxants and indocyanin green occurred almost simultaneously. Pulmonary first-pass retention was negligible. The retention of muscle relaxants at 95% passage of indocyanin green was -9% (-31 to 18%). The difference in the mean transit time between muscle relaxant and indocyanin green was 1.0 (0.8 to 1.4), 0.2 (-0.8 to 0.3), 0.3 (0.2 to 0.4), 0.5 (0.2 to 1.3), and -2.2 s for rocuronium, vecuronium, Org 9487, Org 7617, and d-tubocurarine, respectively. Conclusions There is no substantial pulmonary first-pass uptake of rocuronium, vecuronium, Org 9487, Org 7617, or d-tubocurarine in pigs. Therefore, differences in pulmonary first-pass uptake do not contribute to the differences in potency and/or onset time among muscle relaxants.

scholarly journals Kinetic Modelling of [68Ga]Ga-DOTA-Siglec-9 in Porcine Osteomyelitis and Soft Tissue Infections

Molecules ◽  
2019 ◽  
Vol 24 (22) ◽  
pp. 4094 ◽  
Author(s):  
Lars Jødal ◽  
Anne Roivainen ◽  
Vesa Oikonen ◽  
Sirpa Jalkanen ◽  
Søren B. Hansen ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Hind Limb ◽  
Kinetic Modelling ◽  
Compartment Model ◽  
Cell Surface Expression ◽  
Soft Tissue Infections ◽  
Tissue Samples ◽  
Tissue Compartment ◽  
Arterial Blood ◽  
Kinetics Of

Background: [68Ga]Ga-DOTA-Siglec-9 is a positron emission tomography (PET) radioligand for vascular adhesion protein 1 (VAP-1), a protein involved in leukocyte trafficking. The tracer facilitates the imaging of inflammation and infection. Here, we studied the pharmacokinetic modelling of [68Ga]Ga-DOTA-Siglec-9 in osteomyelitis and soft tissue infections in pigs. Methods: Eight pigs with osteomyelitis and soft tissue infections in the right hind limb were dynamically PET scanned for 60 min along with arterial blood sampling. The fraction of radioactivity in the blood accounted for by the parent tracer was evaluated with radio-high-performance liquid chromatography. One- and two-tissue compartment models were used for pharmacokinetic evaluation. Post-mortem soft tissue samples from one pig were analysed with anti-VAP-1 immunofluorescence. In each analysis, the animal’s non-infected left hind limb was used as a control. Results: Tracer uptake was elevated in soft tissue infections but remained low in osteomyelitis. The kinetics of [68Ga]Ga-DOTA-Siglec-9 followed a reversible 2-tissue compartment model. The tracer metabolized quickly; however, taking this into account, produced more ambiguous results. Infected soft tissue samples showed endothelial cell surface expression of the Siglec-9 receptor VAP-1. Conclusion: The kinetics of [68Ga]Ga-DOTA-Siglec-9 uptake in porcine soft tissue infections are best described by the 2-tissue compartment model.

Quantification of Cerebral A1 Adenosine Receptors in Humans using [18F]CPFPX and PET

2004 ◽  
Vol 24 (3) ◽  
pp. 323-333 ◽  
Author(s):  
Philipp T Meyer ◽  
Dirk Bier ◽  
Marcus H Holschbach ◽  
Christian Boy ◽  
Ray A Olsson ◽  
...  
Keyword(s):  
Compartment Model ◽  
Graphical Analysis ◽  
Attractive Alternative ◽  
The Novel ◽  
Tissue Compartment ◽  
Arterial Blood ◽  
Positron Emission ◽  
Pet Scanning ◽  
Kinetics Of

Adenosine is an important neuromodulator. Basic cerebral effects of adenosine are exerted by the A1 adenosine receptor (A1AR), which is accessible in vivo by the novel ligand [18F]8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine ([18F]CPFPX) and positron emission tomography (PET). The present study investigates the applicability of kinetic models to describe the cerebral kinetics of [18F]CPFPX in order to quantify A1AR density in vivo. Six healthy volunteers underwent dynamic PET scanning and arterial blood sampling after bolus injection of [18F]CPFPX. For quantitative analysis, a standard two-tissue compartment model (2TCM) was compared with a one-tissue compartment model (1TCM) and Logan's graphical analysis (GA). The 2TCM described the cerebral kinetics of [18F]CPFPX significantly better than the 1TCM (in all regions and subjects examined). The estimated values of the regional total distribution volumes ( DVt) correlated strongly between the 2TCM and GA (linear regression r2 = 0.99, slope: 1.007). The DVt correlation between the 2TCM and the 1TCM was comparably high, but there was a significant bias towards lower DVt estimates given by the 1TCM (r2: 0.99, slope: 0.929). It is concluded that a 2TCM satisfactorily accounts for the cerebral kinetics of [18F]CPFPX. GA represents an attractive alternative method of analysis.

Kinetics of pulmonary angiotensin-converting enzyme activity in conscious developing lambs

1984 ◽  
Vol 57 (4) ◽  
pp. 1158-1166 ◽  
Author(s):  
B. R. Pitt ◽  
G. Lister
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Maximum Velocity ◽  
Indicator Dilution ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme Activity ◽  
Alveolar Hypoxia ◽  
Pass Through ◽  
The Right ◽  
Kinetics Of ◽  
Indicator Dilution Techniques

Apparent enzyme kinetics were determined for pulmonary angiotensin-converting enzyme (ACE) as a function of postnatal development and alveolar hypoxia in intact conscious lambs (9 newborn and 7 sheep, 8–23 wk). We injected into the right atrium a mixture of indocyanine green and 3H-labeled benzoyl-phenylalanyl-alanyl-proline (BPAP), a synthetic substrate for ACE, and sampled blood from the aorta at 1-s intervals. From this, we quantified the %BPAP metabolism during a single pass through the lungs by use of indicator-dilution techniques. By adding unlabeled BPAP to the injectate, combining outflow data from two to three measurements, and applying a nonlinear model of pulmonary metabolism (J. Appl. Physiol.: Respirat. Environ. Exercise Physiol. 51:405–414, 1981), we could determine 1) apparent maximum velocity (Vmax); 2) concentration at which velocity was one-half Vmax (Km); and 3) alpha, a measure of perfusion heterogeneity. All animals were studied during normoxia and while breathing 10% O2 for at least 15 min. Seven of the newborn lambs were studied 1 wk later. Km in the newborn was 15 +/- 3 microM and did not change significantly with age or hypoxia. Vmax increased markedly with development (newborn: 14 +/- 2 nmol X s-1 X g dry lung-1; sheep: 38 +/- 5 nmol X s-1 X g dry lung-1; P less than 0.01). Alveolar hypoxia significantly decreased Vmax in the newborn only (P less than 0.05); there was no significant change in Vmax in the same animal studied 1 wk later or in the older group.(ABSTRACT TRUNCATED AT 250 WORDS)

Diffusion and solubility factors in pulmonary inert gas exchanges

1961 ◽  
Vol 16 (5) ◽  
pp. 831-836 ◽  
Author(s):  
Francis P. Chinard ◽  
Theodore Enns ◽  
Mary F. Nolan
Keyword(s):  
Diffusion Coefficients ◽  
Inert Gases ◽  
Limiting Factor ◽  
Gas Exchanges ◽  
Arterial Blood ◽  
Concentration Time ◽  
Anesthetized Dogs ◽  
The Right ◽  
Alveolar Capillary ◽  
Made In

Comparisons have been made in anesthetized dogs of the relative recoveries in arterial blood of pairs of inert gases injected as solutions into the right heart or as gas mixtures into the trachea. The gases differed in their diffusion coefficients or in their solubility. The pairs used were: tritium and Kr85; ethylene-C14 and Xe133. The ratios of the recoveries of the gases approached the ratios of their solubilities and not the ratios of their diffusion coefficients. The site of injection had no significant effect. The concentration-time curves remain proportional during the first passage through the lungs. Diffusion equilibrium is attained within the time of passage of blood through the alveolar capillary. There is no evidence of a diffusion limitation on the exchange of gases with diffusion coefficients as small as that of xenon. Solubility is the limiting factor. Submitted on April 12, 1961

Pulmonary Disposition of Propofol in Surgical Patients

2000 ◽  
Vol 93 (4) ◽  
pp. 986-991 ◽  
Author(s):  
Yan-Ling He ◽  
Hiroshi Ueyama ◽  
Chikara Tashiro ◽  
Takashi Mashimo ◽  
Ikuto Yoshiya
Keyword(s):  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Back Diffusion ◽  
Blood Samples ◽  
Arterial Blood ◽  
Pulmonary Uptake ◽  
Human Lungs ◽  
Infusion Study ◽  
Significant Difference ◽  
First Pass

Background The lungs have been mentioned as a possible site contributing to the extrahepatic clearance of propofol. The objective of the present study was to clarify the pulmonary disposition of propofol directly in human lungs by investigating both the first-pass uptake and pulmonary extraction at pseudo-steady state. Methods Nine patients were enrolled in the first-pass uptake study. Propofol (5 mg) and indocyanine green (ICG; 15 mg) were simultaneously administered via a central venous catheter within 1 s, and sequential arterial blood samples were obtained from the radial artery at 1-s intervals up to 45 s. Eleven patients were included in the infusion study, and propofol was infused via the jugular vein at a rate of 50 microgram. kg-1. min-1. Blood samples were simultaneously collected from pulmonary and radial arteries up to 60 min. Results A pronounced difference in the dilution curves between propofol and ICG was observed, and 28.4 +/- 11.6% (mean +/- SD) of propofol was taken up during the single passage through the human lung. The mean pulmonary transit time of propofol (31.3 +/- 6.0 s) was significantly longer than that of ICG (22.4 +/- 2.7 s; P < 0.01), indicating that some of the propofol trapped by lungs returned to the circulation by back diffusion. In the constant infusion study, no significant differences were observed with the plasma concentrations of propofol between pulmonary and radial arteries except for that at 2 min. The area under the curve of pulmonary and radial arterial concentration curves to 60 min were 59.1 +/- 14.8 and 56.8 +/- 12.5 microg. ml-1. min-1, respectively. No significant difference was observed with the area under the curve, suggesting that metabolism was not involved in the pulmonary uptake in human lungs. Conclusions Most of the propofol that undergoes pulmonary uptake during the first pass was released back to the circulation by back diffusion. Metabolism was not involved in the pulmonary uptake in human lungs.

Ketamine Distribution Described by a Recirculatory Pharmacokinetic Model Is Not Stereoselective 

1999 ◽  
Vol 91 (6) ◽  
pp. 1733-1733 ◽  
Author(s):  
Thomas K. Henthorn ◽  
Tom C. Krejcie ◽  
Claus U. Niemann ◽  
Cheri Enders-Klein ◽  
Colin A. Shanks ◽  
...  
Keyword(s):  
Tissue Distribution ◽  
Drug Transport ◽  
Tissue Perfusion ◽  
Volume Of Distribution ◽  
Peripheral Tissue ◽  
Peripheral Compartment ◽  
Pulmonary Tissue ◽  
Arterial Blood ◽  
Pulmonary Uptake ◽  
Elimination Clearance

Background Differences in the pharmacokinetics of the enantiomers of ketamine have been reported. The authors sought to determine whether these differences extend to pulmonary uptake and peripheral tissue distribution and to test the hypothesis that tissue distribution of the stereoisomers differs because of carrier-mediated drug transport. Methods The dispositions of markers of intravascular space and blood flow (indocyanine green, ICG) and total body water and tissue perfusion (antipyrine) were determined along with S-(+)- and R-(-)-ketamine in five mongrel dogs. The dogs were studied while anesthetized with 2.0% halothane. Marker and drug dispositions were described by recirculatory pharmacokinetic models based on frequent early and less-frequent later arterial blood samples. These models characterize pulmonary uptake and the distribution of cardiac output into parallel peripheral circuits. Results Plasma elimination clearance of the S-(+)-ketamine enantiomer, 29.9 ml x min(-1) x kg(-1), was higher than that of the R-(-)-enantiomer, 22.2 ml x min(-1) x kg(-1). The apparent pulmonary tissue volumes of the ketamine S-(+) and R-(-)-enantiomers (0.31 l) did not differ and was approximately twice that of antipyrine (0.16 l). The peripheral tissue distribution volumes and clearances and the total volume of distribution (2.1 l/kg) were the same for both stereoisomers when elimination clearances were modeled from the rapidly equilibrating peripheral compartment. Conclusions Although the elimination clearance of S-(+)-ketamine is 35% greater than that of the R-(-)-enantiomer, there is no difference in the apparent pulmonary tissue volume or peripheral tissue distribution between the stereoisomers, suggesting that physicochemical properties of ketamine other than stereoisomerism determine its perfusion-limited tissue distribution.

Formulation-dependent Brain and Lung Distribution Kinetics of Propofol in Rats

1998 ◽  
Vol 89 (3) ◽  
pp. 678-685. ◽  
Author(s):  
Sandeep Dutta ◽  
William F. Ebling
Keyword(s):  
Plasma Concentrations ◽  
Pulmonary Sequestration ◽  
Arterial Circulation ◽  
Time Profiles ◽  
Arterial Blood ◽  
Concentration Time ◽  
Distribution Kinetics ◽  
Arterial Concentration ◽  
Emulsion Formulation ◽  
Kinetics Of

Background Propofol when administered by brief infusion in a lipid-free formulation has a slower onset, prolonged offset and greater potency compared with an emulsion formulation. To understand these findings the authors examined propofol brain and lung distribution kinetics in rats. Methods Rats were infused with equieffective doses of propofol in emulsion (n = 21) or lipid-free formulation (n = 21). Animals were sacrificed at various times to harvest brain and lung. Arterial blood was sampled repeatedly from each animal until sacrifice. Deconvolution and moment analysis were used to calculate the half-life for propofol brain turnover (BT) and brain:plasma partition coefficient (Kp). Lung concentration-time profiles were compared for the two formulations. Results Peak propofol plasma concentrations for the lipid-free formulation were 50% of that observed for emulsion formulation, whereas peak lung concentrations for lipid-free formulation were 300-fold higher than emulsion formulation. Brain Kp calculated from tissue disposition curve and ratio of brain:plasma area under the curves were 8.8 and 13, and 7.2 and 9.1 for emulsion and lipid-free formulations, respectively. BT were 2.4 and 2.5 min for emulsion and lipid-free formulations, respectively. Conclusions Significant pulmonary sequestration and slow release of propofol into arterial circulation when administered in lipid-free vehicle accounts for the lower peak arterial concentration and sluggish arterial kinetics relative to that observed with the emulsion formulation. Higher Kp for the lipid-free formulation could explain the higher potency associated with this formulation. BT were independent of formulation and correlated with values reported for effect-site equilibration half-time consistent with a distribution mechanism for pharmacologic hysteresis.

Kinetics of radiolabeled neutrophils in swine

1989 ◽  
Vol 66 (4) ◽  
pp. 1881-1885 ◽  
Author(s):  
M. Ohgami ◽  
C. M. Doerschuk ◽  
D. English ◽  
P. M. Dodek ◽  
J. C. Hogg
Keyword(s):  
Right Atrium ◽  
Indicator Dilution ◽  
Pulmonary Vasculature ◽  
Dilution Technique ◽  
First Passage ◽  
Pass Through ◽  
The Right ◽  
Kinetics Of ◽  
Percent Extraction ◽  
Pulmonary Intravascular Macrophages

The kinetics of radiolabeled neutrophils (PMNs) as they pass through the lungs of swine were evaluated and compared with those in rabbits (J. Appl. Physiol. 63: 1806–1815, 1987) and dogs (J. Appl. Physiol. 63: 1253–1261, 1987; 65: 1217–1225, 1988) previously reported from our laboratory. 111In-labeled PMNs (111In-PMNs) and 99mTc-labeled erythrocytes were simultaneously injected into the right atrium, and the 111In-PMN percent extraction on the first passage through the lung was determined by the indicator-dilution technique. After 10 min of circulation the distribution of 111In-PMNs in selected organs was determined. The extraction of 111In-PMNs in swine was 88 +/- 3%, which was significantly greater than that of rabbits (78 +/- 3%) or dogs (72 +/- 2%). The recovery of the 111In-PMNs in the lungs of swine was 60 +/- 7%, which was two to three times higher than the recovery in lungs of rabbits or dogs. These results show that radiolabeled PMNs injected intravenously are less able to pass through the pulmonary vasculature and are retained much more within the lung in swine than in rabbits or dogs. This difference could be the result of the presence of pulmonary intravascular macrophages in the lungs of swine.

Demonstration and Quantitation of Pharmacological Inhibition of Pulmonary Uptake of N-lsopropyl-123l-p-lodoamphetamine by Propranolol

1989 ◽  
Vol 28 (03) ◽  
pp. 100-104 ◽  
Author(s):  
S. F. Akber
Keyword(s):  
Binding Sites ◽  
Bolus Injection ◽  
Cell Function ◽  
Lung Pathology ◽  
Lung Uptake ◽  
Pharmacological Inhibition ◽  
Sensitive Index ◽  
Pulmonary Uptake ◽  
First Pass

The first-pass pulmonary extraction values of N-lsopropyl-123l-p-lodoamphetamine (123I-IMP) in pretreated dogs decreases from 90 to 62% as the amount of propranolol increases from 0 to 20 mg. The first-pass pulmonary extraction values of 123I-IMP in dogs with a simultaneous bolus injection of propranolol decreases from 90 to 62% as the amount of propranolol increases from 0 to 10 mg. The pulmonary extraction of 123I-IMP with a simultaneous bolus injection of ketamine and 123I-IMP decreases from 90 to 64% as the ketamine dose increases from 0 to 100 mg. These results suggest that the pulmonary uptake of 123I-IMP may be at least partially mediated by receptors. They also indicate that endothelial metabolic cell function may be a useful index of early lung pathology. Furthermore, studies of the degree of lung uptake may be a sensitive index of pathologic states in which alterations of amine binding sites have occurred.

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