Physiological compartments

While these models simulate the transfer of lead between many of the same physiological compartments, they use different methodologies to quantify lead exposure as well as the kinetics of lead transfer among the compartments. As described earlier, in contrast to PBPK models, classical pharmacokinetic models are calibrated to experimental data using transfer coefficients that may not have any physiological correlates. Examples of lead models that use PBPK and classical pharmacokinetic approaches are discussed in the following section, with a focus on the basis for model parameters, including age-specific blood flow rates and volumes for multiple body compartments, kinetic rate constants, tissue dosimetry,... 

F. Stain-Texier, P. Sandouk, J. M. Scherrmann, Intestinal Absorption and Stability of Morphine 6-Glucuronide in Different Physiological Compartments of the Rat , Drug Metab. Dispos. 1998, 26, 383 - 387. 

Additional studies or pertinent information which lend support to this MRL Inhaled metallic mercury is quickly absorbed through the lungs into the blood. Its biologic half-life in humans is approximately 60 days, with the half-life varying with the physiological compartment (e.g., 21 days in the head, versus 64 days in the kidneys Cherian et al. 1978). Since the duration of exposure does influence the level of mercury in the body, the exposure level reported in the Fawer et al. (1983) occupational study was extrapolated from an 8-hour/day, 40-hour/workweek exposure to a level equivalent to a continuous 24 hour/day, 7 days/week exposure as might be encountered near a hazardous waste site containing metallic mercury. 

Ionic forms of iron (referred to hereafter as iron) also participate in a variety of enzymatic reactions as nonheme irons, which are present as iron-sulfur clusters (e.g., mitochondrial electron transport). There are also both storage and transportable forms of iron that are bound to proteins. Under normal physiological conditions only trace amounts of free iron exist. In the body, if iron exceeds the sequestration capacity of the iron-binding proteins present in different physiological compartments, the free iron can cause tissue damage. Cellular injury is caused by reactive oxygen species that are produced from H2O2 in a reaction catalyzed by iron. Thus, iron homeostasis in the body is in a delicate balance. Either the deficiency or the excess results in abnormalities and presents as a common cause of human diseases. 

Transfer is dependent on the rate of blood flow through the physiological compartment. 

A Biomodel component where we specify the molecular species involved in the biological model, the physiological compartments in which they reside, and their interactions. 

The physiological compartments of PBPK models are arranged and connected according to anatomical intercompartment blood flows, and the kinetics in each compartment is described by individual mass-balance differential equations. In the simplest case, it is assumed that mass transfer is blood flow limited and compartments are well-stirred spaces. Under this assumption, the rate of change of concentration (C) in a noneliminating tissue (T) maybe described by the following ordinary differential equation ... 

More problematic and more controversial is the biological role of uteroferrin. Present in allantoic fluid in concentrations often exceeding 2 mg/ml (5 X 10" M), it is hard to imagine an enzymatic function for this protein in the physiological compartment in which it abounds. Conceivably, it is simply leaked into the allantoic fluid by hyperproducing lining cells of the allantoic membrane, for which uteroferrin functions as a lysosomal acid phosphatase ). An alternative possibility is that uteroferrin functions not as an enzyme, since it is almost inactive at the pH of the fluid in which it is found, but as a carrier of iron from sow to fetal pig ). 

Fig. 9. Lead absorption in humans. Numbers in the physiologic compartment boxes are the relative percentage (%) of the body burden and the biological mean-life of lead in that compartment. (Data from Rabinowitz et al. 1973,1976,1977.)...

Chemicals that are taken up into the bloodstream are distributed into various physiological compartments of the body. Examples of physiological compartments are water, fat, and bone. Physiological compartments do not refer to specific organs or anatomical structures. Rather, they are based on the physical-chemical characteristics of tissues, regardless of where in the body the tissues are located. Thus, the fat compartment refers to all fatty tissues everywhere in the body, the water compartment refers to the many parts of the body made up of water, and the bone compartment refers to all bones. A chemical s distribution into physiological compartments... 

The initial steep portion of the time-concentration cnrve in Figure 6.8 shows how quickly a chemical is distributed and reaches a steady state between its concentration in tissues and its concentration in blood. The second, shallower portion of the curve can be used to determine the volume of distribution, the total volume of all the physiological compartments in which a chemical is distributed. Just as physiological compartments of the body are virtual compartments, a chanical s volume of distribution, (j, is a virtual volume. The is defined as the ratio of the total amount of chemical in the body divided by the concentration of the chemical in the plasma (watery) fraction of blood ... 

While the initial phase of the blood concentration-time curve of an intravenously administered chemical reflects its distribution into physiological compartments, the shallow phase reflects its elimination by the kidneys and/or the Uver. Despite its physiological complexity, the elimination of many (though not aU) chanicals from the bloodstream follows first-order kinetics. This means that equal fractions of a chemical disappear from the blood per unit time. A first-order kinetic process is described by an exponential equation ... 

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