Cardiopulmonary parameters and organ blood flows for workers expressed in terms of VO2 for use in physiologically based toxicokinetic modeling

2022 ◽  
pp. 1-29
Author(s):  
Pierre Brochu ◽  
Jessie Ménard ◽  
Sami Haddad
Keyword(s):  
Blood Flows ◽  
Physiologically Based

Simulation of differential drug pharmacokinetics under heat and exercise stress using a physiologically based pharmacokinetic modeling approach

2011 ◽  
Vol 89 (5) ◽  
pp. 365-382 ◽  
Author(s):  
Pardeep Sidhu ◽  
Henry T. Peng ◽  
Bob Cheung ◽  
Andrea Edginton
Keyword(s):  
Oral Administration ◽  
Pharmacokinetic Model ◽  
Heat Exposure ◽  
Area Under The Curve ◽  
Exercise Stress ◽  
Physiologically Based Pharmacokinetic Model ◽  
Blood Flows ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based ◽  
Drug Pharmacokinetics

Under extreme conditions of heat exposure and exercise stress, the human body undergoes major physiological changes. Perturbations in organ blood flows, gastrointestinal properties, and vascular physiology may impact the body’s ability to absorb, distribute, and eliminate drugs. Clinical studies on the effect of these stressors on drug pharmacokinetics demonstrate that the likelihood of pharmacokinetic alteration is dependent on drug properties and the intensity of the stressor. The objectives of this study were to use literature data to quantify the correlation between exercise and heat exposure intensity to changing physiological parameters and further, to use this information for the parameterization of a whole-body, physiologically based pharmacokinetic model for the purposes of determining those drug properties most likely to demonstrate altered drug pharmacokinetics under stress. Cardiac output and most organ blood flows were correlated with heart rate using regression analysis. Other altered parameters included hematocrit and intravascular albumin concentration. Pharmacokinetic simulations of intravenous and oral administration of hypothetical drugs with either a low or high value of lipophilicity, unbound fraction in plasma, and unbound intrinsic hepatic clearance demonstrated that the area under the curve of those drugs with a high unbound intrinsic clearance was most affected (up to a 130% increase) following intravenous administration, whereas following oral administration, pharmacokinetic changes were smaller (<40% increase in area under the curve) for all hypothetical compounds. A midazolam physiologically based pharmacokinetic model was also used to demonstrate that simulated changes in pharmacokinetic parameters under exercise and heat stress were generally consistent with those reported in the literature.

A Physiologically Based, Recirculatory Model of the Kinetics and Dynamics of Propofol in Man

2005 ◽  
Vol 103 (2) ◽  
pp. 344-352 ◽  
Author(s):  
Richard N. Upton ◽  
Guy Ludbrook
Keyword(s):  
Management Strategies ◽  
Compartment Model ◽  
The Body ◽  
Data Sets ◽  
Blood Flows ◽  
Two Compartment Model ◽  
Physiologically Based ◽  
Kinetics And Dynamics ◽  
In Series ◽  
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.

PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELS FOR ADULT AND PAEDIATRIC CHRONIC HEART FAILURE PATIENTS USING THE EXAMPLE OF CARVEDILOL TREATED PATIENTS

2015 ◽  
Vol 101 (1) ◽  
pp. e1.45-e1
Author(s):  
Muhammad Rasool ◽  
Feras Khalil ◽  
Stephanie Läer
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Population Based ◽  
Oral Drug ◽  
Hepatic Extraction ◽  
Blood Flows ◽  
Physiologically Based Pharmacokinetic ◽  
Error Range ◽  
Physiologically Based ◽  
Absorption Phase

BackgroundIn chronic heart failure (CHF), the changes in organ blood flows can significantly affect the metabolism of drugs with high hepatic extraction. Physiologically based pharmacokinetic modelling (PBPK) can be utilized to predict clearances of high extraction drugs like carvedilol in CHF. The adult PBPK-CHF model after its evaluation in adults, can be scaled to pediatrics using population based PBPK simulator.MethodsAfter a literature search for model input parameters, two-PBPK models were developed which differed only on the basis of clearance as, model-1 was based on human liver and intestinal microsomes clearance and model-2 was based on cytochrome-P450 clearances. Developed models were evaluated in healthy adults and in adult CHF patients, after incorporation of reduced organ blood flows. The evaluated adult CHF models were finally scaled to pediatric CHF patients using population based simulator Simcyp®. A two-fold error range for the ratios(Obs/Pred) of the pharmacokinetic parameters was used for model evaluation.ResultsThe prediction results from both models were within the 2-fold error range but the initial absorption phase after oral drug application was slightly over predicted with model-1 on the other hand, the model-2 efficiently captured the oral absorption phase. The CL/F ratios(Obs/Pred) were clearly improved after incorporation of reduced organ blood flows in adult CHF patients. In pediatrics CHF patients, improvement in predictions were seen only in adolescents above 17 years of age, staged with NYHA system of classification.ConclusionThere was a clear link between reduced organ blood flows and reduced carvedilol clearance in adult patients with CHF. It was suggested that Ross scoring system in pediatrics was not well correlated with organ blood flow reductions as the NYHA classification system. Due to the mechanistic nature of the developed models, they can be extended to other drugs with high hepatic extraction.The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement n°602295 (LENA) and from the Faculty Development Program BZ University Multan, Pakistan.

COMPARISON OF ANTIHYPERTENSIVE EFFECT OF MOXONIDINE VERSUS CLONIDINE IN RENAL FAILURE PATIENTS.

2018 ◽  
Vol 6 (9) ◽  
Author(s):  
DR.MATHEW GEORGE ◽  
DR.LINCY JOSEPH ◽  
MRS.DEEPTHI MATHEW ◽  
ALISHA MARIA SHAJI ◽  
BIJI JOSEPH ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Renal Failure ◽  
Blood Flow ◽  
Blood Vessel ◽  
Blood Vessels ◽  
High Blood Pressure ◽  
Antihypertensive Effect ◽  
The Body ◽  
Ability To Work ◽  
Blood Flows

Blood pressure is the force of blood pushing against blood vessel walls as the heart pumps out blood, and high blood pressure, also called hypertension, is an increase in the amount of force that blood places on blood vessels as it moves through the body. Factors that can increase this force include higher blood volume due to extra fluid in the blood and blood vessels that are narrow, stiff, or clogged(1). High blood pressure can damage blood vessels in the kidneys, reducing their ability to work properly. When the force of blood flow is high, blood vessels stretch so blood flows more easily. Eventually, this stretching scars and weakens blood vessels throughout the body, including those in the kidneys.

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