Tissue partition coefficient

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). 

Physiological parameters for volumes and blood flow of the compartments are listed in Table 2-4. Physiologic constants (compartment volume, blood flows, etc) were taken from published values. Values for the solubility of n-hexanc in blood and tissues (partition coefficients) are taken from human tissue (Perbellini et al. 1985). Rate constants (Table 2-4, Figure 2-5) were estimated from animal and human data and are all assumed to be first-order. 

Gearhart JM, Seckel C, Vinegar A. 1993. In vivo metabolism of chloroform in B6C3Fi mice determined by the method of gas uptake the effects of body temperature on tissue partition coefficients and metabolism. Toxicol Appl Pharmacol 119(2) 258-66. 

In a first stage, distribution was predicted with tissue composition-based equations and the estimated tissue partition coefficients were combined with clearance estimated by direct scaling of hepatocyte intrinsic clearance in a PBPK model as described earlier. 

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). 

The thickness of the tissue, partition coefficient, and the diffusion coefficient are properties of the mucosa and cannot be altered. Designing appropriate formulations that heed the necessary conditions can vary the surface area for delivery of the drug, time of contact, and the free drug concentration. The partitioning of the drug into the membrane will depend on... 

Thrall, K.D., R.A. Gies, J. Muniz, A.D. Woodstock, and G. Higgins. 2002. Route-of-entry and brain tissue partition coefficients for common superfund contaminants. J. Toxicol. Environ. Health A. 65(24) 2075-2086. 

METHODOLOGIES TO PREDICT BLOOD AND TISSUE PARTITION COEFFICIENTS... 

Parameter Values Aside from the dependent and independent variables in the equations above, a variety of parameters must be specified. These include physiological parameters (e.g., ventilation rates, cardiac output, organ volumes and masses), physicochemical parameters (e.g., tissue partition coefficients, protein binding constants), and biochemical parameters (e.g., Km and Vmax). 

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. 

Dixon et al. (2001) described a preliminary PB-PK model to predict JP-8 concentrations in Air Force fuel-cell maintenance workers. The model used data from PB-PK models of naphthalene inhalation in mice and rats and nonane inhalation in rats. In addition to inhalation, a pathway of dermal exposure and a skin compartment were included. For highly exposed people, the PB-PK model was generally in agreement with exhaled-air naphthalene concentrations however, predictions for the low-exposure scenarios were grossly underestimated, especially in female workers, by a factor of 10. The model did not predict blood and urinary concentrations. The major limitation of the Dixon et al. (2001) study was the lack of appropriate human data (e.g., metabolic measures, blood and tissue partition coefficients, and diffusion rates). The Dixon et al. (2001) model predicted a rapid decline in naphthalene concentrations in all compartments after exposure except liver, fat, and brain. The model predicted accumulation in liver, brain, and fat tissues for a 7-day period that included 4-hr exposures on 5 days. Competition for enzyme does not occur only from interactions of different inhaled compounds. Interactions can also occur between inhaled compounds and metabolites formed in the body that require similar enzymes for biotransformation. Detailed kinetic studies with both benzene and -hexane show inhibition of later metabolic steps, phenol to hydroquinone or methyl -butyl ketone to 2,5-hexane dione, by high concentrations of inhaled benzene or hexane, respectively (Medinsky et al. 1989 Andersen and Clewell 1984). 

There are two types of parameters that can be employed to represent the extent of distribution in PK models. The first is a tissue partition coefficient Kj), and the second is a volume of distribution (F). The definition of each of these parameters is provided in the following sections. 

Thus plots of In(Ai) and 61( 2) versus time should both have terminal line regions with a slope of —A2-Graphical representations of Ai and In(Ai) versus time are provided in Figure 10.56, and A2 and 61( 2) versus time are provided in Figure 10.57. The relative magnitudes of Ai and A2 depend on the tissue partition coefficients of the tissues included in compartment 2. Thus A2 values could be lower than Ai values at aU times, or the A2 values could rise above the Ai values as the curves approach their terminal line regions. 

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. 

Murphy JE, Janszen DB, Gargas ML. 1995. An in vitro method for determination of tissue partition coefficients of non-volatile chemicals such as 2,3,7,8-tetrachlorodibenzo-p-dioxin and estradiol. JAppl Toxicol 15 147-152. 

The generic structures, technical names, physical and chemical properties, and tissue partition coefficients of the 15 pyrethroids and their metabolites are provided in Tables D1-D15 of Appendix D. Physical property values for modeling were obtained using a 2D model, ACD 12 (Advanced Chemistry Development, Inc., Toronto, Canada). A QSAR 3D model (i.e., QikProp 3.0 (Schrodinger, LL)), used in the development of (fraction unbound to plasma protein), indicated that the differences in physical binding properties between isomers were small. Differences, however, exist in chemical properties as noted in metabolism studies reviewed in Sect. 5. Biotransformation and elimination paths for the pyrethroids that are presented in Tables E1-E15 of Appendix E incorporate preliminary metabolic rate data for PBPK/PD model development. 

PP biadipose Blood adipose tissue partition coefficient... 

Appendix D Chemical Structures, Physical Parameters, and Tissue Partition Coefficients of Parent Pyrethroids and Metabolites... 

Table D1 Oiemical structure, physical and chemical properties, and tissue partition coefficients for Allethrin and resulting metabolites...

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