Computer simulation of a generalized pharmacodynamic model for mammals Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/9k41zj01f

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  • A generalized modeling system was developed for digital computer simulation of the pharmacodynamic response of selected chemicals introduced into mammalian systems. The modeling system is based on the compartmental approach used extensively in pharmacodynamic studies in which the mammal is assumed to be subdivided into compartments which interact by means of blood and other fluid flow according to the actual anatomical and physiological characteristics. Executive routines are provided to automatically formulate and solve all differential equations required in all subregions of all compartments. Utility routines are provided to facilitate rapid input and output of data and results. Complex simulations can be performed for a variety of situations with minimal computer programming by the user. The model of each compartment consists of transport fluid, interstitial and intracellular subregions. Any number of transport fluid subregions in series can be specified which interact with a single interstitial subregion. The interstitial subregion also interacts with any number of specified intracellular subregions. Provision is made for combining any or all of the subregions with the interstitial subregion in the absence of mass transfer resistance between that subregion and the interstitial fluid in order to reduce numerical computation time. Chemical reaction can occur by Michealis-Menten kinetics in any subregion. Source and excretion of chemical must be defined by specially written routines by the user of the generalized modeling system. Equilibrium protein binding of chemical can occur on protein binding sites which are specified by data input. The generalized pharmacodynamic modeling system was tested by reproducing several pharmacodynamic studies reported in the literature. In addition, the uptake and distribution of methyl mercury in rats was modeled using the generalized system. The model was constructed with six compartments: blood, liver, kidney, muscle, GI, and other tissue. No resistance to mass transfer was assumed between the transport fluid and the interstitial subregion. Methyl mercury was assumed to be bound to hemoglobin and albumin in blood and to albumin only in the interstitial subregion. The binding of methyl mercury to protein in the various tissue and the mass transfer coefficients between interstitial and intracellular subregions were adjusted to promote agreement between model and experimental tissue distribution data due to the lack of this information. Excretion of methyl mercury in feces was modeled by assuming that fecal excretion included ten percent of the methyl mercury in the bile from the liver in addition to the excretion by exfoliation of the epithelial cells of the small intestine. Excretion of methyl mercury in urine was assumed to be proportional to the concentration of methyl mercury in the cells of the kidney. Good agreement was obtained between the model and the experimental data of Dr. Fang (1976).
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