Partitioning blood-tissue

Other important determinants of the effects of compounds, especially solvents, are their partition coefficients, e.g., blood-tissue partition coefficients, which determine the distribution of the compound in the body. The air-blood partition coefficient is also important for the absorption of a compound because it determines how quickly the compound can be absorbed from the airspace of the lungs into the circulation. An example of a compound that has a high air-blood partition coefficient is trichloroethane (low blood solubility) whereas most organic solvents (e.g., benzene analogues) have low air-blood partition coefficients (high blood solubility). 

Maximum binding capacity of erythrocytes Half-saturation concentration Partition coefficients for blood/tissue kinetics Blood/liver Blood/kidney... 

Blood-tissue uptake rates (l< ) can often be approximated from data at early (t < 10 minutes) time points in IV studies, provided the blood has been washed from the organ (e.g., liver) or the contribution from blood to the tissue residue is subtracted (fat). High accuracy is not usually required since these parameters can be optimized to fit the data when they are used in more complex models. Tissue-blood recycling rates (A y) and residence times can be computed from partition coefficients if estimates of uptake rates are available. 

After whole-body autoradiography to study the distribution of " C-labeled chloroform in mice, most of the radioactivity was found in fat immediately after exposure, while the concentration of radioactivity in the liver increased during the postanesthetic period, most likely due to covalent binding to lipid and protein in the liver (Cohen and Hood 1969). Partition coefilcients (tissue/air) for mice and rats were 21.3 and 20.8 for blood 19.1 and 21.1 for liver 11 and 11 for kidney and 242 and 203 for fat, respectively (Corley et al. 1990). Arterial levels of chloroform in mongrel dogs reached 0.35-0.40 mg/mL by the time animals were in deep anesthesia (Chenoweth et al. 1962). Chloroform concentrations in the inhaled stream were not measured, however. After 2.5 hours of deep anesthesia, there were 392 mg/kg chloroform in brain tissue, 1,305 mg/kg in adrenals, 2,820 mg/kg in omental fat, and 290 mg/kg in the liver. 

The inhalational anesthetics have distinctly different solubility (affinity) characteristics in blood as well as in other tissues. These solubility differences are usually expressed as coefficients and indicate the number of volumes of a particular agent distributed in one phase, as compared with another, when the partial pressure is at equilibrium (Table 25.3). For example, isoflurane has a blood-to-gas partition coefficient (often referred to as the Ostwald solubility coefficient) of approximately 1.4. Thus, when the partial pressure has reached equilibrium, blood will contain 1.4 times as much isoflurane as an equal volume of alveolar air. The volume of the various anesthetics required to saturate blood is similar to that needed to saturate other body tissues (Table 25.3) that is, the blood-tissue partition coefficient is usually not more than 4 (that of adipose tissue is higher). 

Drugs are not only eliminated via the kidneys but also eliminated in the bile by the liver and metabolized in the liver and elsewhere, which makes direet measurement of the elimination rate of a drug diffieult. Indeed, other routes of elimination eould inelude loss in expired air, saliva, sweat, partition into tissue stores, efflux from the blood into the gut lumen, and gut metabolism as well as other sites of metabolism sueh as the lung. The total clearance, CL, ean be defined as... 

Different approaches have been published regarding the prediction of partition coefficients on the basis of physicochemical parameters of compounds [26-29], These authors described algorithms for the estimation of blood-air and tissue-blood partition coefficients. The most important descriptor for blood-tissue partitioning appears to be lipophilicity and can be described as a function of blood and tissue composition with regard to the lipid and water fractions. Charged molecules do not easily pass membranes passively however, weak bases appear to interact with the charges present at the hydrophilic moieties of phospholipids and can be transferred over the membranes in this way [28]. 

Once the structure of the PBPK model is formulated, the next step is specifying the model parameters. These can be classified into a chemical-independent set of parameters (such as physiological characteristics, tissue volumes, and blood flow rates) and a chemical-specific set (such as blood/tissue partition coefficients, and metabolic biotransformation parameters). Values for the chemical-independent parameters are usually obtained from the scientific literature and databases of physiological parameters. Specification of chemical-specific parameter values is generally more challenging. Values for one or more chemical-specific parameters may also be available in the literature and databases of biochemical and metabolic data. Values for parameters that are not expected to have substantial interspecies differences (e.g., tissue/blood partition coefficients) can be imputed based on parameter values in animals. Parameter values can also be estimated by conducting in vitro experiments with human tissue. Partitioning of a chemical between tissues can be obtained by vial equilibration or equilibrium dialysis studies, and metabolic parameters can be estimated from in vitro metabolic systems such as microsomal and isolated hepatocyte syterns. Parameters not available from the aforementioned sources can be estimated directly from in vivo data, as discussed in Section 43.4.5. 

Many of the cells in tissues are embedded in an extracellular matrix that fills the spaces between cells and binds cells and tissue together. In so doing, the extracellular matrix aids in determining the shape of tissues as well as the nature of the partitioning between tissue types. In the skin, loose connective tissue beneath epithelial cell layers consists of an extracellular matrix in which fibroblasts, blood vessels, and other components are distributed (Fig 49.1). Other types of connective tissue, such as tendon and cartilage, consist largely of extracellular matrix, which is principally responsible for their structure and function. This matrix also forms the sheetlike basal laminae, or basement membranes, on which layers of epithelial cells rest, and which act as supportive tissue for muscle cells, adipose cells, and peripheral nerves. 

Lung parameters (pulmonary and alveolar ventilation, pulmonary perfiision, air-blood coefficient, blood-tissue coefficient). These coefficients describe the amount of solvents which can diffuse. The blood-tissue partition coefficient influences the tissue equilibrium concentrations. Solvents with stronger hydrophobic properties (e.g., toluene) reach equilibrium more rapidly because of a low tissue-blood coefficient Intraindividual differences such as child/adult are also of significance. 

Abraham MH. 2014. A simple method for estimating in vitro air-tissue and in vivo blood-tissue partition coefficients. Chemosphere 120C 188-191. 

Abraham MH, Gola JMR, Ihrahim A, Acree WE, Liu X. 2014. The prediction of blood-tissue partitions, water-skin partitions and skin permeation for agrochemicals. PestManag Sci 70 1130-1137. 

This interpretation is in conflict with some published discussions of the source of bone carbonate, which suggest that bone carbonate gives us a sample of energy somces (Krueger and Sulhvan 1984), by which is meant carbohydrates and fats (e.g., Ambrose and Norr 1993). It should be clear from the previous discussion that very little partitioning of carbon somces can occm. Bicarbonate in the blood is derived from essentially all the carbon atoms in the diet, including proteins, in proportion to their abimdance in the diet all foods are energy sources . Minor deviations from this arise due to (1) Tissue... 

Physiologically Based Phamiacokinetic (PBPK) Model—Comprised of a series of compartments representing organs or tissue groups with realistic weights and blood flows. These models require a variety of physiological information tissue volumes, blood flow rates to tissues, cardiac output, alveolar ventilation rates and, possibly membrane permeabilities. The models also utilize biochemical information such as air/blood partition coefficients, and metabolic parameters. PBPK models are also called biologically based tissue dosimetry models. 

Estimation methods for tissue-to-blood partition coefficients (i.e., Rt) have been the most prolific, no doubt due to the need for this parameter in most organ models. Both in vitro and in vivo parameter estimation techniques are available. 

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