Liver-blood partition coefficients

Graphs of Log DpH 7.4 vs. Adipose Tissue Blood and Liver 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. 

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... 

Fig. 9 Liver blood and fat blood partition coefficients of allethrin and metabolites are plotted as a function of ACD Log DpH 7.4. Equation (14), involving ACD Log DpH 7.4, was used to calculate the partition coefficients for liver. Equation (16), involving the conversion of ACD LogDpH 7.4 to log D vo w, was used to calculate the partition coefficients for fat. To correct for protein binding, the nonadipose and adipose tissue equations (14) and (16) were multiplied by fup/fut derived from equations (22) and (23) (see Table 6). The Henderson-Hasselbach equations were not used. Allethrin and its metabolites are identified in Table D1 (Appendix D)...

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

Partition coefficients of a series of aliphatic hydrocarbons, including n-hexane, have been determined in human tissues (Perbellini et al. 1985). The following partition coefficients for n-hexane (olive oil/air, blood/air, tissue/air) were determined olive oil, 146 blood, 0.80 liver, 5.2 kidney, 3 brain, 5 fat, 104 muscle, 5 heart, 2.8 and lung, 1. Saline/air partition was not reported separately for n-hexane, but was very low for the range reported for the entire group of compounds (0.1-0.4). 

Partition coefficients for -hcxanc in male Fischer 344 rats have been reported (blood/air, tissue/air) blood, 2.29 liver, 5.2 muscle, 2.9 and fat, 159 (Gargas et al. 1989). 

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. 

The specific mechanisms by which mirex and chlordecone are transferred from the gut, lungs, or skin to the blood are not known. However, mirex is a highly stable, lipophilic compound that is resistant to metabolism. It has a high lipid water partition coefficient, so it partitions readily into fat and demonstrates a very high potential for accumulation in tissues. The preferential distribution of chlordecone to the liver rather than to the fat tissue is due to its association with plasma proteins. 

Chloroform is lipid soluble and readily passes through cell membranes, causing narcosis at high concentrations. Blood chloroform concentrations during anesthesia (presumed concentrations 8,000-10,000 ppm) were 7-16.2 mg/mL in 10 patients (Smith et al. 1973). An arterial chloroform concentration of 0.24 mg/mL during anesthesia corresponded to the following partition coefficients blood/gas, 8 blood/vessel rich compartment, 1.9 blood/muscle compartment, 1.9 blood/fat compartment, 31 blood/vessel poor compartment, 1 and blood/liver, 2 (Feingold and Holaday 1977). Recently, partition coefficients were calculated for humans based on results in mice and rats, and in human tissues in vitro blood/air, 7.4 liver/air, 17 kidney/air, 11 and fat/air, 280 (Corley et al. 1990). 

Physiological toxicokinetic models have been presented describing the behaviour of inhaled butadiene in the human body. Partition coefficients for tissue air and tissue blood, respectively, had been measured directly using human tissue samples or were calculated based on theoretical considerations. Parameters of butadiene metabolism were obtained from in-vitro studies in human liver and lung cell constituents and by extrapolation of parameters from experiments with rats and mice in vivo (see above). In these models, metabolism of butadiene is assumed to follow Michaelis-Menten kinetics. 

Male Fischer 344/N rats were exposed via the nose only for 6 h to concentrations of vinylidene fluoride ranging from 27 to 16 000 ppm [71-42 000 mg/m. Tidal volume (mean, 1.51 mL/brcath) and respiratory frequency (mean, 132 breaths/min) were not influenced by exposure concentration. Steady-state blood levels of vinylidene fluoride increased linearly with increasing exposure concentration up to 16 000 ppm. Vinylidene fluoride tissue/air partition coefficients were determined experimentally to be 0.07, 0.18, 0.8,10, and 0.29 for water, blood, liver, fat and muscle, respectively. Previously published detenninations (Filser Bolt, 1979) for the maximum velocity of metabolism in mg/li/kg) and Michaelis Menten constant (K in mg/L) are 0.07 and 0.13, respectively. Time to reach steady-state blood levels of vinylidene fluoride was less than 15 min for all concentrations. After cessation of exposure, blood levels of vinylidene fluoride decreased to 10% of steady-state levels within 1 h. Simulation of the metabolism of vinylidene fluoride mdicated that although blood levels of vinylidene fluoride increased linearly with increasing exposure concentration, the amount of vinylidene fluoride metabolized per 6-h exposure period approached a maximum at about 2000 ppm [5240 mg/m vinylidene fluoride (Medinsky et al., 1988). 

There are several physiochemical properties of the toxicant that can influence its distribution. These include lipid solubility, pKa, and molecular weight, all of which were described earlier in this chapter (Section 6.4) and will not be described here. For many toxicants, distribution from the blood to tissues is by simple diffusion down a concentration gradient, and the absorption principles described earlier also apply here. The concentration gradient will be influenced by the partition coefficient or rather the ratio of toxicant concentrations in blood and tissue. Tissue mass and blood flow will also have a significant effect on distribution. For example, a large muscle mass can result in increased distribution to muscle, while limited blood flow to fat or bone tissue can limit distribution. The ratio of blood flow to tissue mass is also a useful indicator of how well the tissue is perfused. The well perfused tissues include liver,... 

The lungs are the primary site of elimination for gaseous anesthetics and any other compounds that are volatile. For example, certain aromatic hydrocarbons are largely eliminated in the expired air. The major pathway for the elimination of ethanol, of course, is metabolism by the liver. However, approximately 2 percent is eliminated via the lungs. The equilibrium partition coefficient for ethanol between blood and alveolar air in humans is approximately 2100 1. Therefore, the ethanol concentration in end-expiratory air can be measured and multiplied by 2100 (e.g., by the Breathalyzer machine) to provide a fairly accurate estimate of ethanol concentration in the blood. 

A physiologically based pharmacokinetics (PBPK) model based on the ventilation rate, cardiac output, tissue blood flow rates, and volumes as well as measured tissue/air and blood/air partition coefficients has been developed (Medinsky et al. 1989a Travis et al. 1990). Experimentally determined data and model simulations indicated that during and after 6 hours of inhalation exposure to benzene, mice metabolized benzene more efficiently than rats (Medinsky et al. 1989a). After oral exposure, mice and rats appeared to metabolize benzene similarly up to oral doses of 50 mg/kg, above which rats metabolized more benzene than did mice on a per kg body weight basis (Medinsky et al. 1989b). This model may be able to predict the human response based on animal data. Benzene metabolism followed Michaelis-Menton kinetics in vivo primarily in the liver, and to a lesser extent in the bone marrow. Additional information on PBPK modeling is presented in Section 2.3.5. 

Disposition in the Body. Rapidly absorbed upon inhalation blood gas partition coefficient about 2.4. It accumulates in adipose tissue. About 60 to 80% of an absorbed dose is exhaled unchanged from the lungs in 24 hours and smaller amounts continue to be exhaled for several days or weeks. A variable amount is metabolised in the liver by debromination and dechlorination replacement of a fluorine atom by a methoxy group followed by glucuronic acid conjugation occurs to a limited extent. Other metabolites which have been detected in expired air and in blood are 2-chloro-1,1,1-trifluoroethane and 2-chloro-l, 1-difluoroethylene. Up to about 20% of a dose may be excreted in the urine as trifluoroacetic acid and its salts. Bromide ion is slowly excreted in the urine. 

Absorption is very rapid after inhalation and reaches a steady state within minutes of exposure and blood levels decline rapidly at the end of exposure. Biotransformation is very slow difluoroethylene may produce alkylating intermediate and some acetone. The tissue/air partition coefficients were determined to be 0.07, 0.18, 0.8, 1.0, and 0.29 for water, blood, liver, fat, and muscle, respectively. Difluoroethylene is eliminated as fluoride ions in urine. 

The second set of parameters are compound specific and will determine its transport over barriers (e.g., between gut and blood, blood and tissues), its biotransformation, and its excretion. Most of the transport parameters can be described as partition coefficients [20] and are strongly determined by the compound s physicochemical parameters, lipophilicity and volatility being the most important ones. However, the role of transporter proteins present in cellular membranes and responsible for the partitioning over specific barriers needs special attention, e.g., in the gut, the kidney, and at the blood-brain barrier [22], the blood placenta barrier, and the liver-bile interface [23]. 

Physiologic parameters used, biochemical constants, and partition coefficients in the model are shown in Table 2-9. Physiologic constants (organ volume, blood flows, etc.) and tissue and blood coefficients were taken from literature sources (Astrand 1983 Fiserova-Bergerova 1983a). Elimination constants for the liver were taken from experiments in the perfused rat liver (Johanson et al. 1986b). Venous equilibrium was assumed, and competitive inhibition between ethanol and 2-butoxyethanol was assumed. 

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