Investigation of 5-FU disposition after oral administration of capecitabine, a triple-prodrug of 5-FU, using a physiologically based pharmacokinetic model in a human cancer xenograft model: comparison of the simulated 5-FU exposures in the tumour tissue between human and xenograft model

2001 ◽  
Vol 22 (1) ◽  
pp. 1-14 ◽  
Author(s):  
Yuko Tsukamoto ◽  
Yukio Kato ◽  
Masako Ura ◽  
Ikuo Horii ◽  
Tohru Ishikawa ◽  
...  
Keyword(s):  
Oral Administration ◽  
Model Comparison ◽  
Pharmacokinetic Model ◽  
Human Cancer ◽  
Xenograft Model ◽  
Tumour Tissue ◽  
Physiologically Based Pharmacokinetic Model ◽  
Physiologically Based Pharmacokinetic ◽  
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.

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