Download - Transport of Pharmocokinetic Agent in the Myocardium Xianfeng Song Sima Setayeshgar Feb. 16, 2004
Transport of Pharmocokinetic Agent in the Myocardium
Xianfeng SongSima Setayeshgar
Feb. 16, 2004
Pericardial Delivery: Motivation The pericardial sac is a fluid-filled self-contained space (10ml – 50ml for
human) surrounding the heart. As such, it can be potentially used therapeutically as a “drug reservoir”
Use of pericardial space for delivery of agents (antiarrhythmic, gene therapy) to Coronary vasculature Myocardium
Recently experimental feasibility Verrier VL, Waxman S, Lovett EG, Moreno R. Transatrial access to the
normal pericardial space: a novel approach for diagnostic sampling, pericardiocentesis and therapeutic interventions. Circulation, 1998; 98:2331-2333
Stoll HP, Carlson K, Keefer LK, Hrabie JA, March KL. Pharmacokinetic and consistency of pericardial delivery directed to coronary arteries: direct comparison with endoluminal delivery. Clin Cardiol, 1999; 22(Suppl-I): I-10-I-16
Outline
Experiments on juvenile farm pigs to measure the spatial concentration profile in the myocardium of agents placed in the pericardial space
Mathematical Modeling to investigate the efficacy of agent penetration in myocardial tissue, extract the key physical parameters
Preliminary Results
Conclusions
Experiments Performed by Hans-Peter Stoll, M.D., Keith L. March, M.D., Ph.D.,
Indiana University-Purdue University Indianapolis Medical School
Experimental subjects: juvenile farm pigs
Method: radiotracer method to determine the spatial concentration profile
Radioiodinated test agents Insulin-like Growth Factor (125I-IGF, MW: 7740) Basic Fibroblast Growth Factor (125I-bFGF, MW: 18000)
Brief Introduction of Experimental Procedure
Mathematical ModelGoals
Investigate the efficacy of agent penetration in myocardium
Extract the key physical parametersDetermine appropriate drug quantities and expected
time course of delivery
The key physical processesSubstrate transport across boundary layer between
pericardial sac and myocardium: αSubstrate diffusion in myocardium: DTSubstrate washout through the vascular and lymphatic
capillaries in myocardium: k
Idealized Spherical Geometry
Pericardial sac: R2 – R3
Myocardium: R1 – R2
“Chambers”: 0 – R1
R1 =2.5cmR2 =3.5cmVolume of Pericardial sac:
10ml-40ml
Governing Equations and Boundary conditions
Governing equation in myocardium
CT: concentration of agent in tissue DT: effective diffusion constant in tissue k: washout rate Consider pericardial sac as a drug reservoir (Well mixing and no washout of drug
in pericardial sac)
The drug current flowed through the boundary layer between pericardial sac and myocardium is proportional to the concentration difference between them
Fit to experiments
Fitting Error surface
Fit to experiments (Rough results)
Time-course from simulation
Parameters: DT=7×10-6cm2s-1 k=5×10-4s-1 α=3.2×10-
6cm2s2
D* in tortuous media Fluctuation-dissipation theory D: diffusion constant R: hydrodynamic radius v: T: temperature
In tortuous media
D*: diffusion constant in tortuous media D: diffusion constant in fluid λ: tortuosity
In myocardium, λ=2.11 (M. Suenson, D.R. Richmond, J.B. Bassingthwaighte, Diffusion of sucrose, sodium, and water in ventricular myocardium, American Joural of Physiology, Vol 227, No. 5, Nov. 1974 )
Estimate the diffusion constant IGF bFGF
Our fitted values are in order of 10-6 cm2sec-1
Contradiction?
Speculation on mixing due to viscoelastic motion of heart
The tissue is a porous medium consisting of extracellular space and muscle fibers. The extracellular space consists of an incompressible fluid (mostly water)
Effective stirring: the expansion and contraction of the muscle cells leads to changes in the pore sizes and therefore mixing of the extracellular volume. This effective "stirring" could be responsible for the larger diffusion constants.
ConclusionModel is consistent with experiments despite its
simplicity
The effective diffusion constants for two drugs (IGF,bFGF) are both in the order of
The wash out rate for both drugs are in the order of
……
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