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.

scholarly journals Physiologically Based Pharmacokinetic Models of Probenecid and Furosemide to Predict Transporter Mediated Drug-Drug Interactions

2020 ◽  
Vol 37 (12) ◽  
Author(s):  
Hannah Britz ◽  
Nina Hanke ◽  
Mitchell E. Taub ◽  
Ting Wang ◽  
Bhagwat Prasad ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Organic Anion ◽  
Plasma Concentrations ◽  
Whole Body ◽  
Time Profiles ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Concentration Time ◽  
Anion Transporter ◽  
Physiologically Based

Abstract Purpose To provide whole-body physiologically based pharmacokinetic (PBPK) models of the potent clinical organic anion transporter (OAT) inhibitor probenecid and the clinical OAT victim drug furosemide for their application in transporter-based drug-drug interaction (DDI) modeling. Methods PBPK models of probenecid and furosemide were developed in PK-Sim®. Drug-dependent parameters and plasma concentration-time profiles following intravenous and oral probenecid and furosemide administration were gathered from literature and used for model development. For model evaluation, plasma concentration-time profiles, areas under the plasma concentration–time curve (AUC) and peak plasma concentrations (Cmax) were predicted and compared to observed data. In addition, the models were applied to predict the outcome of clinical DDI studies. Results The developed models accurately describe the reported plasma concentrations of 27 clinical probenecid studies and of 42 studies using furosemide. Furthermore, application of these models to predict the probenecid-furosemide and probenecid-rifampicin DDIs demonstrates their good performance, with 6/7 of the predicted DDI AUC ratios and 4/5 of the predicted DDI Cmax ratios within 1.25-fold of the observed values, and all predicted DDI AUC and Cmax ratios within 2.0-fold. Conclusions Whole-body PBPK models of probenecid and furosemide were built and evaluated, providing useful tools to support the investigation of transporter mediated DDIs.

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.

Microcomputer-assisted metabolic studies of voluntary diving of Weddell seals

1986 ◽  
Vol 250 (2) ◽  
pp. R175-R187 ◽  
Author(s):  
M. Guppy ◽  
R. D. Hill ◽  
R. C. Schneider ◽  
J. Qvist ◽  
G. C. Liggins ◽  
...  
Keyword(s):  
Specific Activity ◽  
Plasma Concentrations ◽  
Diving Response ◽  
Decay Kinetics ◽  
Descending Aorta ◽  
Weddell Seals ◽  
Arterial Blood ◽  
Organ Specific ◽  
Clearance Kinetics ◽  
Kinetics Of

Utilizing a microprocessor-controlled peristaltic withdrawal pump, arterial blood samples were obtained from Weddell seals (Leptonychotes weddelli) while diving voluntarily under the sea ice at McMurdo Sound, Antarctica. Plasma concentrations of glucose, lactate, free fatty acids, urea, and amino acids were determined in seals at various times during rest, diving, and recovery. In addition, radiolabeled palmitate, glucose, lactate, p-aminohippurate, inulin, galactose, and cholate were injected into the descending aorta of seals in the resting state or during voluntary diving at sea. Sequential plasma samples were collected, and the kinetics of wash-in and clearance of each component were determined. Under resting conditions, the change in specific activity of palmitate, glucose, and lactate after bolus injection followed smooth multiexponential decay kinetics as in terrestrial animals. Similar decay curves for the clearance of organ-specific compounds were also obtained in seals at rest. If, during voluntary diving, Weddell seals were analogous to exercising animals, the wash-in and clearance kinetics of all metabolites and organ-specific compounds would be qualitatively similar to those observed at rest. In contrast, wash-in and clearance appeared to be qualitatively and quantitatively modified in a way consistent with utilization of the classical Scholander diving response in both short and long dives.

scholarly journals Colistin Methanesulfonate Is an Inactive Prodrug of Colistin against Pseudomonas aeruginosa

2006 ◽  
Vol 50 (6) ◽  
pp. 1953-1958 ◽  
Author(s):  
Phillip J. Bergen ◽  
Jian Li ◽  
Craig R. Rayner ◽  
Roger L. Nation
Keyword(s):  
Pseudomonas Aeruginosa ◽  
High Performance ◽  
Time Course ◽  
Antimicrobial Activities ◽  
Killing Effect ◽  
Time Profiles ◽  
Concentration Time ◽  
Colistin Methanesulfonate ◽  
Kinetics Of ◽  
Hydrolysis Of

ABSTRACT There is a dearth of information on the pharmacodynamics of “colistin,” despite its increasing use as a last line of defense for treatment of infections caused by multidrug-resistant gram-negative organisms. The antimicrobial activities of colistin and colistin methanesulfonate (CMS) were investigated by studying the time-kill kinetics of each against a type culture of Pseudomonas aeruginosa in cation-adjusted Mueller-Hinton broth. The appearance of colistin from CMS spiked at 8.0 and 32 mg/liter was measured by high-performance liquid chromatography, which generated colistin concentration-time profiles. These concentration-time profiles were subsequently mimicked in other incubations, independent of CMS, by incrementally spiking colistin. When the cultures were spiked with CMS at either concentration, there was a substantial delay in the onset of the killing effect which was not evident until the concentrations of colistin generated from the hydrolysis of CMS had reached approximately 0.5 to 1 mg/liter (i.e., ∼0.5 to 1 times the MIC for colistin). The time course of the killing effect was similar when colistin was added incrementally to achieve the same colistin concentration-time course observed from the hydrolysis of CMS. Given that the killing kinetics of CMS can be accounted for by the appearance of colistin, CMS is an inactive prodrug of colistin with activity against P. aeruginosa. This is the first study to demonstrate the formation of colistin in microbiological media containing CMS and to demonstrate that CMS is an inactive prodrug of colistin. These findings have important implications for susceptibility testing involving “colistin,” in particular, for MIC measurement and for microbiological assays and pharmacokinetic and pharmacodynamic studies.

scholarly journals Microdialysis-directed Intra-tumor Pharmacokinetic Modeling of Methotrexate in Mice and Humans

2016 ◽  
Vol 19 (2) ◽  
pp. 239 ◽  
Author(s):  
Helal H. Alsulimani ◽  
Jonghan Kim ◽  
Shabnam N. Sani
Keyword(s):  
Time Course ◽  
Pharmacokinetic Model ◽  
Plasma Concentrations ◽  
Human Tumor ◽  
Physiological Data ◽  
Time Profiles ◽  
Tumor Bearing ◽  
Forcing Function ◽  
Physiologically Based Pharmacokinetic ◽  
Concentration Time

Purpose. To develop a quantitative pharmacokinetic model to characterize the disposition of methotrexate (MTX) at tumor site in tumor-bearing mice and to predict MTX concentrations in the human tumor. Methods. The plasma profiles of MTX were obtained from normal mice, while microdialysis technique was employed to characterize the time course of MTX in tumor from breast tumor-bearing mice. Disposition profiles of plasma and tumor were analyzed by a hybrid physiologically-based pharmacokinetic (hPBPK) model that incorporates physiologically-relevant parameters such as tumor blood flow and volume, while plasma concentrations were used as a forcing input into the vascular-interstitial spaces of the tumor. The plasma profiles were initially described by a biexponential decay model to obtain a forcing function that enters into the vascular-interstitial spaces in the tumor. Using a defined forcing function, the tumor free concentrations were fitted to the hPBPK model. Based on the model developed, sensitivity analysis was conducted with a perturbation of PK parameters to predict different scenarios of intratumoral MTX transport. The relevant physiological PK parameters from the mouse model were then scaled-up and utilized to simulate human tumor concentrations. Results. The mouse hPBPK model adequately characterized the concentration-time profiles of MTX in both plasma and tumor and produced various transfer rate constants between plasma and tumor. Our model was also able to reasonably predict MTX concentrations in the human tumor when human physiological data were utilized. Conclusions. The hPBPK model was able to quantitatively characterize the atypical transport of MTX in the tumor, supporting the idea that microdialysis is a valuable tool to study tumor biodistribution of drugs and to predict tumor concentrations in humans based on the pre-clinical data. This information can ultimately aid in the development of anticancer drugs with improved PK profiles. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

Nitrate and chloride formation in chloramination

1994 ◽  
Vol 30 (9) ◽  
pp. 101-110
Author(s):  
V. Diyamandoglu
Keyword(s):  
Kinetic Model ◽  
Analytical Method ◽  
Kinetic Data ◽  
Experimental Results ◽  
Mass Balances ◽  
Time Profiles ◽  
Slow Decay ◽  
Concentration Time ◽  
End Products ◽  
Chlorine Residuals

The formation of nitrate and chloride as end-products of chloramination (combined chlorination) was investigated at pH ranging between 6.9 and 9.6 at 25°C. The experimental results comprised concentration-time profiles of combined chlorine residuals along with nitrate and chloride. Nitrite, if present, was always below the detectibility limit of the analytical method used (25 ppb). Mass balances on chlorine species depicted that chloride formed during the slow decay of combined chlorine residuals does not account for all the chlorine lost. This substantiates the formation of other reaction end-products which are yet to be identified. A kinetic model for chloramination is proposed based on the kinetic data obtained in this study.

Interphase distribution of 2-furylethylenes

1985 ◽  
Vol 50 (8) ◽  
pp. 1642-1647 ◽  
Author(s):  
Štefan Baláž ◽  
Anton Kuchár ◽  
Ernest Šturdík ◽  
Michal Rosenberg ◽  
Ladislav Štibrányi ◽  
...  
Keyword(s):  
Partition Coefficient ◽  
Partition Coefficients ◽  
Transport Rate ◽  
Phase System ◽  
Two Phase ◽  
Interphase Distribution ◽  
Distribution Kinetics ◽  
System 1 ◽  
Kinetics Of

The distribution kinetics of 35 2-furylethylene derivatives in two-phase system 1-octanol-water was investigated. The transport rate parameters in direction water-1-octanol (l1) and backwards (l2) are partition coefficient P = l1/l2 dependent according to equations l1 = logP - log(βP + 1) + const., l2 = -log(βP + 1) + const., const. = -5.600, β = 0.261. Importance of this finding for assesment of distribution of compounds under investigation in biosystems and also the suitability of the presented method for determination of partition coefficients are discussed.

scholarly journals The Effect of Bilateral Nephrectomy on Renalase and Catecholamines in Hemodialysis Patients

2021 ◽  
Vol 18 (12) ◽  
pp. 6282
Author(s):  
Magda Wiśniewska ◽  
Natalia Serwin ◽  
Violetta Dziedziejko ◽  
Małgorzata Marchelek-Myśliwiec ◽  
Barbara Dołęgowska ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Plasma Concentrations ◽  
Serum Levels ◽  
Hemodialysis Patients ◽  
Pressure Regulation ◽  
Serum Concentrations ◽  
Monoamine Oxidase Activity ◽  
Normal Kidney ◽  
Bilateral Nephrectomy ◽  
Arterial Blood

Background/Aims: Renalase is an enzyme with monoamine oxidase activity that metabolizes catecholamines; therefore, it has a significant influence on arterial blood pressure regulation and the development of cardiovascular diseases. Renalase is mainly produced in the kidneys. Nephrectomy and hemodialysis (HD) may alter the production and metabolism of renalase. The aim of this study was to examine the effect of bilateral nephrectomy on renalase levels in the serum and erythrocytes of hemodialysis patients. Methods: This study included 27 hemodialysis patients post-bilateral nephrectomy, 46 hemodialysis patients without nephrectomy but with chronic kidney disease and anuria and 30 healthy subjects with normal kidney function. Renalase levels in the serum and erythrocytes were measured using an ELISA kit. Results: Serum concentrations of renalase were significantly higher in post-bilateral nephrectomy patients when compared with those of control subjects (101.1 ± 65.5 vs. 19.6 ± 5.0; p < 0.01). Additionally, renalase concentrations, calculated per gram of hemoglobin, were significantly higher in patients after bilateral nephrectomy in comparison with those of healthy subjects (994.9 ± 345.5 vs. 697.6 ± 273.4, p = 0.015). There were no statistically significant differences in plasma concentrations of noradrenaline or adrenaline. In contrast, the concentration of dopamine was significantly lower in post-nephrectomy patients when compared with those of healthy subjects (116.8 ± 147.7 vs. 440.9 ± 343.2, p < 0.01). Conclusions: Increased serum levels of renalase in post-bilateral nephrectomy hemodialysis patients are likely related to production in extra-renal organs as a result of changes in the cardiovascular system and hypertension.

Sign in / Sign up

Export Citation Format

Share Document