Tissue-blood partition coefficients

Tissue blood partition coefficients (R ) should be determined when steady-state has been achieved. Estimates based on samples obtained during the elimination phase following a single dose of the test substance may lead to underestimates of this ratio in both eliminating and noneliminating tissues unless its half-life is very long. Correction of these values for elimination has been described by several authors (Yacobi et al., 1989 Shargel and Yu, 1999 Renwick, 2000). 

Internal burdens of epoxybutene in humans resulting from exposure to butadiene were predicted from models by Kohn and Melnick (1993), Johanson and Filser (1996) and Csanady et al. (1996) and were compared with simulations for rats and mice. In the model of Kohn and Melnick (1993), metabolic parameters were incorporated which had been obtained by Csanady et al. (1992) by measuring butadiene and epoxybutene oxidation and epoxybutene hydrolysis in human liver and lung microsomes in vitro, and conjugation of epoxybutene with glutathione in human liver and lung cytosol. Tissue blood partition coefficients were theoretically derived. The body burden of epoxy butene following exposure to 100 ppm butadiene for 6 h was predicted to be 0.056 pmol/kg in humans. 

In the model of Csanady et al. (1996), the biochemical parameters for butadiene in rats and mice were obtained by fitting model simulations to in-vivo data of Bolt et al. (1984) and Kreiling et al. (1986). The biochemical parameters for epoxybutene were identical to those of Johanson and Filser (1993, 1996). This model accurately predicted experimental data on epoxybutene. The most advanced models are those of Csanady etal. (1996) and Sweeney et al. (1997), since they can simulate both epoxybutene and diepoxybutane as metabolites of butadiene. The tissue blood partition coefficients for diepoxybutane were estimated by Csanady et al. (1996) to have a value of 1 for all tissues. Sweeney et al. (1997) obtained tissue blood partition coefficients from in-vitro measurements (Table 23). Both models yielded good predictions for mice and rats for both metabolites. For humans, no measured data have been reported against which the predictions could be validated. In addition, the model of Csanady et al. (1996) predicted accurately the measured haemoglobin adduct levels (Osterman-Golkar etal., 1993 Albrecht et al., 1993) of epoxybutene in rodents following exposure to butadiene. None of the models published has included the fonnation and elimination of epoxybutanediol. 

Tissue Blood Partition Coefficients Used in the Keys et al. (1999) Model 3-6. Physiological Parameter Values Used in the Keys et al. (1999) Model... 

Tissue blood partition coefficients for DEHP and nonionized MEHP were estimated from their n-octanol water partition coefficients (Kow), using the approach reported by Poulin and Krishnan (1993). 

Tissue blood partition coefficients for total MEHP (ionized and nonionized) were determined experimentally using a vial-equilibration method with correction for pH (Table 3-5). 

A model-based dependence of human tissue-blood partition coefficients of chemicals on lipophilidty and tissue composition was recently described [78], For 36 neutral chemicals, the partitioning between seven different tissues and blood in humans was modeled, considering accumulation in the membrane, protein binding, and dis-... 

Balaz, S. and Lukacova, V., A model-based dependence of the human tissue/blood partition coefficients of chemicals on lipophilicity and tissue composition, Quant. Struct.-Act. Relat., 18, 361-368, 1999. 

DeJongh, J., Verhaar, H.J.M., and Hermens, J.L.M., A quantitative property-property (QPPR) approach to estimate in vitro tissue-blood partition coefficients of organic chemicals in rats and humans, Arch. Toxicol., 72, 17-25, 1997. 

Poulin, P. and Krishnan, K., An algorithm for predicting tissue blood partition coefficients of organic chemicals from n-octanol water partition coefficient data, J. Toxicol. Environ. Health, 46, 117-129, 1995. 

Haddad S, Poulin P, Krishnan K. 2000a. Relative lipid content as the sole mechanistic determinant of the adipose tissue blood partition coefficients of highly lipophilic organic chemicals. Chemosphere 40 839-843. 

Ruark, C.D., Hack, C.E. Sterner, T.R., Robinson, P.J., Gearhart, J.M. (2008). Quantitative structure activity relationship (QSAR) for extrapolation of tissue/blood partition coefficients of nerve agents across species. DTRA 16th Biennial Medical Chemical Defense Bioscience Review June 1-6, 2008, Hunt Valley, MD. 

Zhang, H., Zhang, Y. (2006). Convenient nonlinear model for predicting the tissue/blood partition coefficients of seven human tissues of neutral, acidic, and basic structurally diverse compounds. J. Med. Chem. 49 5815-29. 

Maruyama, W., Yoshida, K., Tanaka, T. and Nakanishi, J. (2002) Determination of tissue-blood partition coefficients for a physiological model for humans, and estimation of dioxin concentration in tissues. Chemosphere, 46 (7), 975-985. 

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. 

Biochemical parameters such as tissue/blood partition coefficients can be obtained from in vitro experiments with vial equilibration (18) or equilibrium dialysis techniques (19). A less expensive process involves exploiting the similarities in physical characteristics of similar tissues in animals and humans and using in vitro animal data (20). Other, even more cost-effective techniques include extrapolation from experimentally determined octanol/water partition coefficients (21), or in sUico parameter estimation via techniques based on structure-property relationships (22, 23). 

H. B. Zhang, A new approach for the tissue-blood partition coefficients of neutral and ionized compounds. / Chem Inf Modeling 45 121-127 (2005). 

Since the toxicity of a given PCB mixture is related to its congener composition, congener-specific information on kinetic parameters is necessary if PBPK models are to be used as part of risk assessment. Methods to predict the tissue blood partition coefficient (Parham et al. 1997) and metabolic rate... 

The solubility of the anesthetic in tissue is expressed as the tissue/blood partition coefficient. Because the concentration of the anesthetic in the brain is probably of most interest, however, the... 

Tissue Blood Partition Coefficients Used in the Keys et al. (2000) Model... 

Keys et al. (2000) explored five approaches to modeling the pharmacokinetics of di- -butyl phthalate and mono- -butyl phthalate. In a flow-limited version of the model, transfers between blood and tissues are simulated as functions of blood flow, tissue concentrations of di- -butyl phthalate or mono-n-butyl phthalate, and tissue blood partition coefficients, assuming instantaneous partitioning of the compounds between tissue and blood (Ramsey and Anderson 1984). In an enterohepatic circulation version of the model, the transfer of mono-n-butyl phthalate from the liver to the small intestine is represented with a first order rate constant (diffusion-limited) and a time delay constant for the subsequent reabsorption of mono- -butyl phthalate from the small intestine. In a diffusion-limited version of the model, the tissue transfers include a first order rate term (referred to as the permeation constant) that relates the intracellular-to-extracellular concentration gradient to the rates of transfer. This model requires estimates of extracellular tissue volume (ECV) and intracellular volume (ICV) ECV is assumed to be equal to tissue blood volume and ICV is assumed to be equal to the difference between tissue blood volume and... 

Tissue blood partition coefficients for total and nonionized mono- -butyl phthalate were estimated from their n-octanol water partition coefficients (Kq,), using the approach reported by Poulin and Krishnan (1995). Tissue blood partition coefficients for total mono- -butyl phthalate (ionized and nonionized) were determined experimentally using a vial-equilibration method with correction for pH (Table 3-4). 

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