Models, tissue-blood partition coefficients

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... 

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. 

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. 

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. 

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... 

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... 

Mechanistic models for determining the partitioning of a pesticide between skin and blood are addressed in Sect. 4.4. In this section, blood plasma protein binding (F p) was included in the Poulin-TheU model (2000 2002a b) to calculate tissue blood partition coefficients. This procedure greatly reduces the amount of unbound pesticide in blood that is available for partitioning into adipose tissues. A laboratory method, such as the one developed by Jepson et al. (1992, 1994) and reviewed by Knaak et al. (2008), may be used to determine whether predicted values are correct. 

Knaak et al. (2008) reviewed the literature pertaining to in vitro methods for developing tissue blood partition coefficients for PBPK models. The experimental work of Jepson et al. (1992,1994) is significant. Ultrafiltration was used to develop tissue saline and tissue blood partition coefficients. No new studies of this nature were found during the preparation of this review on pyrethroids. Automated laboratory methods are still needed and must be developed to insure the partition coefficients obtained firom the use of mechanistic or QSAR models are reasonable (Payne and Kenny 2002 Rowland, personal communication). 

Tissue Blood Partition Coefficients QSAR Models... 

Knaak et al. (2008) reviewed the nonlinear QSAR equation developed by Zhang (2005) and the QSAR model developed by Liu et al. (2005a) for predicting tissue blood partition coefficients. To our knowledge, neither the QSAR equations nor models are available in the form of ready-to-use programs for obtaining partition... 

The tables in Appendix E were developed to provide modelers with complete information on the rat metabolic pathway for each of the pyrethroid insecticides. The tables in Appendix D are designed to provide the tissue blood partition coefficients for the parent pyrethroids and their metabolites. Some metabolic rates may not exist for either rat or human metabolic pathways, and hence, modelers may have to zero out this parameter in the PBPK/PD models they work with. In any case, the importance of each metabolic pathway needs to be determined from the enzymes that exist in tissues, their rate constants (i.e., Emax and and the amount or content of each enzyme present. If in vitro enzyme work is to be performed, good analytical methods and analytical samples for each metabolite are essential. 

Tissue blood partition coefficients were developed for the parent pyrethroids and their metabolites, by using a published mechanistic model introduced by Poulin and Thiele (2002a b) and log Dpn 7 4 values. The estimated coefficients, especially those of adipose tissue, were too high and had to be corrected by using a procedure in which the proportion of parent or metabolite residues that are unbound to plasma albumin is considered, as described in the GastroPlus model (SimulationsPlus, Inc., Lancaster, CA). The literature suggested that values be adjusted by multiplying... 

The vial equilibration method is the most common in vitro method for determining partition coefficients for volatile or semivolatile materials and has been used most successfully for volatile organic solvents (Gargas et al., 1988). Tissues are harvested from the species of interest and incubated with the test compoxmd imtil equilibrium is reached between the tissue and the headspace in the vial. The blood/air or tissue/air partition coefficients are given by the ratio of the concentrations of the chemical in the blood or tissue relative to its concentration in the headspace. Tissue-blood partition coefficients are calculated from the respective tissue/air and blood/air values. A number of operational equations have been derived to calculate these ratios xmder specific experimental conditions. Time to steady state is critical and should be optimized for the test compoxmd. Metabolism of the compound in exposed tissue samples must be controlled. Analysis is performed by gas chromatography in a verified linear range. Human tissues can be obtained from tissue bank organizations to provide species specificity to models developed with human data. To estimate... 

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. 

JH Lin, Y Sugiyama, S Awazu, M Hanano. In vitro and in vivo evaluation of the tissue-to-blood partition coefficients for physiological pharmacokinetic models. J Pharmacokin Biopharm 10 637-647, 1982. 

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