Tissue-blood Partition Coefficients Research Articles

Bioconcentration of two basic pharmaceuticals, verapamil and clozapine, in fish.

The present study examined the bioconcentration of 2 basic pharmaceuticals: verapamil (a calcium channel blocker) and clozapine (an antipsychotic compound) in 2 fresh water fishes, fathead minnow and channel catfish. In 4 separate bioconcentration factor (BCF) experiments (2 chemicals × 1 exposure concentration × 2 fishes), fathead minnow and channel catfish were exposed to 190 μg/L and 419 μg/L of verapamil (500 μg/L nominal) or 28.5 μg/L and 40 μg/L of clozapine (50 μg/L nominal), respectively. Bioconcentration factor experiments with fathead consisted of 28 d uptake and 14 d depuration, whereas tests conducted on catfish involved a minimized test design, with 7 d each of uptake and depuration. Fish (n = 4-5) were sampled during exposure and depuration to collect different tissues: muscle, liver, gills, kidneys, heart (verapamil tests only), brain (clozapine tests only), and blood plasma (catfish tests only). Verapamil and clozapine concentrations in various tissues of fathead and catfish were analyzed using liquid chromatography-mass spectrometry. In general, higher accumulation rates of the test compounds were observed in tissues with higher perfusion rates. Accumulation was also high in tissues relevant to pharmacological targets in mammals (i.e. heart in verapamil test and brain in the clozapine test). Tissue-specific BCFs (wet wt basis) for verapamil and clozapine ranged from 0.7 to 75 and from 31 to 1226, respectively. Tissue-specific concentration data were used to examine tissue-blood partition coefficients.

Analysis of the distribution of organic compounds and drugs between biological tissues in the framework of solute partitioning in aqueous two-phase systems.

Partition coefficients of non-ionic essentially nonpolar compounds between air and rat biological tissues and between blood and other tissues were examined and found to be linearly interrelated according to the previously established equation for partition coefficients of solutes in aqueous two-phase systems: log Kblood-tissue-1 = k0 + k1 log Kblood-tissue-2 + k2 log Kblood-tissue-3, where k0, k1, and k2 are constants. Analysis of partition coefficients of amphiphilic and ionizable drugs between blood and different tissues in rats in vivo showed that the above relationship holds for the blood-tissue partition coefficients of these compounds as well. The data obtained indicate that distribution of organic compounds between different biological tissues may be considered in the framework of solute partitioning in aqueous two-phase systems, and imply that aqueous media in different tissues have different solvent properties, and compound-water interactions in these media may respond to different environments governed by the tissue composition.

Using water-solvent systems to estimate in vivo blood-tissue partition coefficients.

BackgroundBlood–tissue partition coefficients indicate how a chemical will distribute throughout the body and are an important part of any pharmacokinetic study. They can be used to assess potential toxicological effects from exposure to chemicals and the efficacy of potential novel drugs designed to target certain organs or the central nervous system. In vivo measurement of blood–tissue partition coefficients is often complicated, time-consuming, and relatively expensive, so developing in vitro systems that approximate in vivo ones is desirable. We have determined such systems for tissues such as brain, muscle, liver, lung, kidney, heart, skin, and fat.ResultsSeveral good (p < 0.05) blood–tissue partition coefficient models were developed using a single water–solvent system. These include blood–brain, blood–lung, blood–heart, blood–fat, blood–skin, water–skin, and skin permeation. Many of these partition coefficients have multiple water–solvent systems that can be used as models. Several solvents—methylcyclohexane, 1,9-decadiene, and 2,2,2-trifluoroethanol—were common to multiple models and thus a single measurement can be used to estimate multiple blood–tissue partition coefficients. A few blood–tissue systems require a combination of two water–solvent partition coefficient measurements to model well (p < 0.01), namely: blood–muscle: chloroform and dibutyl ether, blood–liver: N-methyl-2-piperidone and ethanol/water (60:40) volume, and blood–kidney: DMSO and ethanol/water (20:80) volume.ConclusionIn vivo blood–tissue partition coefficients can be easily estimated through water–solvent partition coefficient measurements.Graphical abstract:Predicted blood-brain barrier partition coefficients coloured by measured log BB valueElectronic supplementary materialThe online version of this article (doi:10.1186/s13065-015-0134-z) contains supplementary material, which is available to authorized users.

Uptake and Tissue Distribution of Pharmaceuticals and Personal Care Products in Wild Fish from Treated-Wastewater-Impacted Streams

A fish plasma model (FPM) has been proposed as a screening technique to prioritize potential hazardous pharmaceuticals to wild fish. However, this approach does not account for inter- or intraspecies variability of pharmacokinetic and pharmacodynamic parameters. The present study elucidated the uptake potency (from ambient water), tissue distribution, and biological risk of 20 pharmaceutical and personal care product (PPCP) residues in wild cyprinoid fish inhabiting treated-wastewater-impacted streams. In order to clarify the uncertainty of the FPM for PPCPs, we compared the plasma bioaccumulation factor in the field (BAFplasma = measured fish plasma/ambient water concentration ratio) with the predicted plasma bioconcentration factor (BCFplasma = fish plasma predicted by use of theoretical partition coefficients/ambient water concentration ratio) in the actual environment. As a result, the measured maximum BAFplasma of inflammatory agents was up to 17 times higher than theoretical BCFplasma values, leading to possible underestimation of toxicological risk on wild fish. When the tissue-blood partition coefficients (tissue/blood concentration ratios) of PPCPs were estimated, higher transportability into tissues, especially the brain, was found for psychotropic agents, but brain/plasma ratios widely varied among individual fish (up to 28-fold). In the present study, we provide a valuable data set on the intraspecies variability of PPCP pharmacokinetics, and our results emphasize the importance of determining PPCP concentrations in possible target organs as well as in the blood to assess the risk of PPCPs on wild fish.

Reply to the comment on “A simple method for estimating in vitro air-tissue and in vivo blood-tissue partition coefficients”

Reply to the comment on “A simple method for estimating in vitro air-tissue and in vivo blood-tissue partition coefficients”

A simple method for estimating in vitro air-tissue and in vivo blood-tissue partition coefficients

A simple method is reported for the estimation of in vivo air-tissue partition coefficients of VOCs and of in vitro blood-tissue partition coefficients for volatile organic compounds and other compounds. Linear free energy relationships for tissues such as brain, muscle, liver, lung, kidney, heart, skin and fat are available and once the Abraham descriptors are known for a compound, no more than simple arithmetic is required to estimate air-tissue and blood-tissue partitions.

Determination of tissue blood partition coefficients for non-volatile herbicides and fungicides using negligible depletion solid phase microextraction (nd-SPME)

Determination of tissue blood partition coefficients for non-volatile herbicides and fungicides using negligible depletion solid phase microextraction (nd-SPME)

Generic parameterization for a pharmacokinetic model to predict Cd concentrations in several tissues of different fish species

In the present work, a set of generic parameters was proposed for a pharmacokinetic model, with the objective of predicting Cd concentration in the tissues of diverse fish species under different environmental conditions. Cd concentrations in a number of tissues of Oncorhynchus mykiss and Cyprinus carpio were estimated by a structurally identifiable multicompartmental model (unique solution). The 13 generic parameters of the model comprised exchange rates, tissue-blood partition coefficients, and weight-corrected elimination rate constants accounting for the routes of water respiration, excretion and egestion. On the other hand, absorption efficiencies from water and food were considered to be condition-specific and estimated for each experiment. These two parameters reflected the differences in fish exposure to diet (food type and metal concentration) or water (water chemistry and bioavailable metal concentration). A data set of 27 experiments of Cd bioaccumulation in fish tissues was compiled for model calibration. The selected dynamics on trout and carp were performed under very different experimental conditions, involving water and/or food exposure, different fish weights and exposure concentrations and the presence/absence of depuration periods. Model predicted, for most compartments and experiments, the tendency of Cd dynamics. However, accumulation in liver and kidney was underestimated in approximately a half of the experiments, due mainly to a rapid metallothionein (MT) sequestration phenomena and subsequent saturation on liver and kidney produced under high exposure concentrations. On the other hand, both generic and condition-specific parameter values were in accordance with the values reported in literature when available. Therefore, the results obtained in this work are an initial step indicating that a generic global input parameter set could be applied to physiology-based pharmacokinetic (PBPK) models for estimating Cd accumulation in fish in different types of scenarios.

Binding of Matrix Metalloproteinase Inhibitors to Extracellular Matrix: 3D‐QSAR Analysis

Binding to the extracellular matrix, one of the most abundant human protein complexes, significantly affects drug disposition. Specifically, the interactions with extracellular matrix determine the free concentrations of small molecules acting in tissues, including signaling peptides, inhibitors of tissue remodeling enzymes such as matrix metalloproteinases, and other drug candidates. The nature of extracellular matrix binding was elucidated for 63 matrix metalloproteinase inhibitors, for which the association constants to an extracellular matrix mimic were reported here. The data did not correlate with lipophilicity as a common determinant of structure-nonspecific, orientation-averaged binding. A hypothetical structure of the binding site of the solidified extracellular matrix surrogate was analyzed using the Comparative Molecular Field Analysis, which needed to be applied in our multi-mode variant. This fact indicates that the compounds bind to extracellular matrix in multiple modes, which cannot be considered as completely orientation-averaged and exhibit structural dependence. The novel comparative molecular field analysis models, exhibiting satisfactory descriptive and predictive abilities, are suitable for prediction of the extracellular matrix binding for the untested chemicals, which are within applicability domains. The results contribute to a better prediction of the pharmacokinetic parameters such as the distribution volume and the tissue-blood partition coefficients, in addition to a more imminent benefit for the development of more effective matrix metalloproteinase inhibitors.

A New Approach for the Tissue−Blood Partition Coefficients of Neutral and Ionized Compounds

A nonlinear model equation based on tissue composition (a content of lipids, proteins, and water) for the tissue-blood partition coefficients of compounds was further developed in this paper to account for the neutral and ionized forms of the compounds. The nonlinear model equation may be considered as the expressive form of the Hansch equation in nonlinear spaces (or multiphase system). Based on this model our nonlinear regression analysis for neutral and ionized compounds partitioning into kidney, brain, muscle, lung, liver, heart, and fat resulted in equations with high fitting power (training set: n=201, r=0.905, s=0.291, Q=0.890) and strong predictive power (test set: n=64, r=0.906, s=0.247). These results showed that the equilibrium distribution of a compound in a variety of tissues is essentially the equilibrium distribution of the compound in tissue (chemical) compositions. Neutral and ionic forms of a compound as well as in different tissue (chemical) compositions have a different mechanism of action in vivo.

Biokinetic and Toxicodynamic Modelling and its Role in Toxicological Research and Risk Assessment

Toxicological risk assessment for chemicals is still mainly based on highly standardised protocols for animal experimentation and exposure assessment. However, developments in our knowledge of general physiology, in chemicobiological interactions and in (computer-supported) modelling, have resulted in a tremendous change in our understanding of the molecular mechanisms underlying the toxicity of chemicals. This permits the development of biologically based models, in which the biokinetics as well as the toxicodynamics of compounds can be described. In this paper, the possibilities are discussed of developing systems in which the systemic (acute and chronic) toxicities of chemicals can be quantified without the heavy reliance on animal experiments. By integrating data derived from different sources, predictions of toxicity can be made. Key elements in this integrated approach are the evaluation of chemical functionalities representing structural alerts for toxic actions, the construction of biokinetic models on the basis of non-animal data (for example, tissue-blood partition coefficients, in vitro biotransformation parameters), tests or batteries of tests for determining basal cytotoxicity, and more-specific tests for evaluating tissue or organ toxicity. It is concluded that this approach is a useful tool for various steps in toxicological hazard and risk assessment, especially for those forms of toxicity for which validated in vitro and other non-animal tests have already been developed.

POSSIBLE RANGE OF DIOXIN CONCENTRATION IN HUMAN TISSUES: SIMULATION WITH A PHYSIOLOGICALLY BASED MODEL

In risk evaluation of dioxins, monitoring chemical concentrations in human tissues is an important step, and these concentration data can be utilized along with animal toxicity data for extrapolation of human manifestation. However large differences in dioxin concentrations usually exist even among individuals who have never been accidentally exposed to high quantities of dioxin, and this may cause problems in risk analysis. Body size, age, and history of food consumption are factors responsible for these interindividual differences in addition to exposure levels. Using a physiologically based pharmacokinetic (PBPK) model, the influence of differences in body weight, gastrointestinal absorption, and half-life and intake of dioxin were examined on tissue chemical concentration. Dioxin concentrations over a 40-yr time course in human liver, kidneys, fat, blood, muscle and richly perfused tissue were simulated for polychlorinated dibenzo- p -dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and coplanar polychlorinated biphenyls (CoPCBs). Model parameters such as tissue-blood partition coefficients for CoPCBs were prepared, and sensitivity analysis was also performed on these parameters. The range of tissue concentrations was approximately 0.17 to 4.1 times the standard concentration, which was calculated using standard model parameters. The simulated ranges included more than 80% of the individual anatomical data for 2,3,7,8-tetrachlorodibenzo- p -dioxin, 1,2,3,7,-pentachlorodibenzo- p -dioxin, and 3,3',4,4',5-pentachlorobiphenyl in liver, fat, and blood. These results suggest that differences in body weight, gastrointestinal absorption, and food intake behavior may partially explain variation in tissue concentrations among individuals, and the possible interindividual uncertainty, which is approximately 24 for the general Japanese population.

COMPARISON OF MODELS FOR THE ESTIMATION OF BIOLOGICAL PARTITION COEFFICIENTS

Several models have been published for calculating blood-air, tissue-air, or tissue-blood partition coefficients of volatile organic chemicals in human or rat tissues, from functions of their octanol-water partition coefficients or solubilities in vegetable oil and water. In this work, the relative accuracy, strengths, and limitations of the various models are examined. Comparison of predicted human tissue-air and tissue-blood partition coefficients with experimental values has been made for 12 chemicals, covering a wide range of lipophilicity (acetone, isopropanol, diethylether, methylene dichloride, benzene, toluene, trichloroethylene, trichloroethane, n-pentane, cyclohexane, n-hexane, and n-heptane). Seven published models for human tissue-air and 10 models for tissue-blood partition coefficients have been compared. Fewer models are available for predicting rat tissue-air and rat tissue-blood partition coefficients, but a similar comparison has been made. The ratio of predicted to experimental partition coefficients and their mean, R mean , and the mean magnitude of the difference between predicted and experimental values of log 10 P, E, were used to assess the accuracy of each model. For the test set the most accurate for human blood-air partition coefficients were the empirical equations of Meulenberg and Vijverberg (R mean = 1.1 - 0.46, E = 0.156) and the empirical solvation equation of Abraham and Weathersby (1994) (R mean = 0.93 - 0.38, E = 0.166). For rat blood, predictions are much less accurate due to difficulties in modeling the effects of protein binding, which are much larger. Overall, for rat blood-air partition coefficients the equation of Meulenberg and Vijverberg (1999) (R mean = 0.74 - 0.50, E = 0.236) was the most accurate. The tissue-composition-based equations of Poulin and Krishnan, using solubilities in vegetable oil, performed well for human liver-air partition coefficients (R mean = 1.21 - 0.28, E = 0.079) for log(octanol-water partition coefficients) > 0.7 and for fat-air partition coefficients, but overestimated solubilities in human kidney and brain tissues (e.g., for kidney tissue, R = 1.88 - 0.58, E = 0.255). The equations of Meulenberg and Vijverberg (2000a), Abraham and Weathersby (1994), and Paterson and Mackay (1989) also performed moderately well for human tissue-air partition coefficients. For rat muscle-air, liver-air, and fat-air partition coefficients the model of Poulin and Krishnan (1996a) gave the most accurate predictions. For tissue-blood partition coefficients, generally good agreement with experimental values is obtained by the empirical model of Balaz and Lukacova (1999) (e.g., for human kidney, R mean = 1.15 - 0.38, E = 0.085) and, if solubility in fat is known, by the equations of Fiserova-Bergerova and Diaz (1986) (e.g., for human muscle, R mean = 1.10 - 0.39, E = 0.107). The equations of DeJongh et al. (1997) gave the most accurate predictions for rat muscle-blood, liver-blood and fat-blood partition coefficients (e.g., for rat muscle R mean = 1.03 - 0.39, E = 0.149), but predictions were less accurate than for human tissue-blood partition coefficients, attributable to difficulties in modeling the effect of protein binding. The choice of equation for use in physiologically based pharmacokinetic (PBPK) models depends on the species, tissue, and chemical lipophilicity.

The applicability of in vitro-derived data in hazard identification and characterisation of chemicals

Toxicological hazard and risk assessments for chemicals presently are mainly based on highly standardised protocols for animal experimentation and exposure assessment. In this paper the possibilities are being discussed of developing systems in which the systemic (acute and chronic) toxicity of chemicals can be quantified, without the heavy reliance on animal experiments. On the basis of a chemical's structure, in vitro data on its toxicity, and biokinetic modelling a decision/flow scheme is presented. Key elements are the evaluation of chemical functionalities representing structural alerts for toxic actions, the construction of biokinetic models on the basis of non-animal data (e.g. tissue–blood partition coefficients (PCs), in vitro biotransformation parameters), tests or batteries of tests for determining basal cytotoxicity and more specific tests for evaluating tissue- or organ toxicity. It is concluded that such a flow chart is a useful tool for different steps in the toxicological hazard and risk assessment, especially for those forms of toxicity for which validated in vitro and other non-animal tests have already been developed.

Tissue solubility of four volatile anesthetics in fresh and frozen tissue specimens from swine

To determine tissue solubilities of desflurane, sevoflurane, enflurane, and halothane in swine and to evaluate the effects of freezing specimens on tissue solubility, Arterial blood samples and specimens of brain, heart, liver, kidney, muscle, and subcutaneous fat from 5 healthy female adult Chinese Meishan pigs. Each tissue specimen was divided into 2 parts. One part was used to measure tissue-gas partition coefficients immediately after collection. The other part was frozen at -20 C for 6 days prior to determination of tissue-gas partition coefficients. Tissue-gas and blood-gas partition coefficients were measured by use of gas chromatography, and tissue-blood partition coefficients were calculated. Regression analysis was performed to determine whether fat-gas partition coefficients were correlated with lean tissue-gas partition coefficients. Tissue-gas and blood-gas partition coefficients of halothane were greater than those of enflurane followed by coefficients of sevoflurane and desflurane. However, the order of anesthetic agents with the greatest to smallest tissue-blood partition coefficients was sevoflurane, halothane, enflurane, and desflurane. Muscle-gas partition coefficients of sevoflurane and enflurane, liver-gas partition coefficients of desflurane and halothane, and the kidney-gas partition coefficient of enflurane were significantly greater in frozen specimens, compared with fresh specimens. Lean tissue-gas partition coefficients of all 4 volatile anesthetics correlated directly with fat-gas partition coefficients. The fat content of lean tissue is an important factor in determining the tissue solubility of volatile anesthetics. Freezing specimens before determination of tissue-gas partition coefficients may result in a false increase in tissue solubility.

Physiologically based pharmacokinetic analyses of simple mixtures.

Exposure to multiple chemicals may cause significant alterations of tissue dose of the toxic moiety of one or more of the individual chemicals. The change in target tissue dose of a chemical present in simple mixtures can be predicted when the determinants of disposition of each chemical, and the mechanism of toxicokinetic interaction between chemicals are understood at a quantitative level. Determinants of disposition include physiological (e.g., breathing rates, cardiac output, tissue volumes, blood flow rates), biochemical (e.g., kinetic constants for metabolism and protein binding), and physicochemical factors (e.g., blood air and tissue blood partition coefficients). Mechanisms of toxicokinetic interactions refer to the manner in which coexposure alters these determinants of disposition as compared to exposure to the individual chemicals. Interactions between chemicals can be described quantitatively with physiologically based pharmacokinetic (PBPK) models, which integrate these mechanic determinants and permit prediction of alterations in tissue dose for various exposure situations by computer simulation. PBPK modeling studies of binary chemical interactions conducted so far indicate that inhibitory rather than potentiating metabolic interactions are more likely to be observed during multiple chemical exposures. As PBPK models of representative binary, tertiary and quaternary mixtures are developed, it will become increasingly possible to draw reliable conclusions about the risk associated with human exposure to chemical mixtures.

Multi-compartment model to study the effect of air-blood and blood-tissue partition coefficients on concentration-time-effect relationships.

The influence of the air-blood (lambda) and blood-tissue partition coefficients of substances on the concentration-time-effect relationship E = [aCnT]b was studied by model simulation of uptake and distribution of gases. The model consisted of a lung compartment and four tissue compartments. Rat and human model parameters were obtained from physiological data, and substance-dependent variables. The observable effect E (righting reflex, mortality, etc.) for directly acting systemic agents was supposed to be related to the (arbitrarily chosen) concentration of the substance in the arterial blood or in the liver compartment. We conclude that for a directly acting systemic agent n greater than or equal to 1. If n less than 1 other mechanisms such as metabolism must be incorporated in the model which, however, should not be excluded when n greater than or equal to 1. If the observable effect is related to arterial concentration of the substance, n increases with decreasing lambda. If the liver concentration is related to the observable effect, man and rat may behave quite differently. This has major consequences for the extrapolation of animal results to the human situation in risk assessment.

Determination of the partition coefficient of 133xenon between oral tissues and blood in the dog

Ostwald solubility coefficients for 133Xe in plasma ( S p), red blood cells ( S c), and selected oral tissue homogenates ( S t) obtained from the dog were determined at 4, 20, 27 and 37 °C by counting the 133Xe activity of the air phase and the sample (liquid, red cells or tissue) in the same tube following equilibration. The partition coefficient for xenon (λ, in ml/g) between red cells and plasma ( λ cp) and that between tissues and plasma ( λ tp) were calculated from the measured S p, S c and S t. The tissue-blood partition coefficients ( λ tb) of oral tissues for 133Xe were then calculated using λ cp, λ tp and the haematocri value. The calculated values of λ tb at 37 °C and 50 per cent haematocrit were 0.650 for the pulp, 0.674 for the tongue, 0.828 for the submandibular gland and 0.881 for the gingiva of the dog. λ cp increased and λ tp decreased as the temperature was reduced from 37 to 4 °C.

Effect of hematocrit on the washout of xenon and iodantipyrine from dog myocardium.

The rates of washout of 133Xe and 131I-iodoantipyrine from the myocardium into the coronary sinus blood were determined over a wide range of hematocrits after simultaneous injection of the isotopes into the left anterior descending coronary artery of dogs. The ratio of the monoexponential disappearance constants (kX/kI), which is a measure of the ratio of the dynamic blood-tissue partition coefficients (lambdabIX/lambdabtI), increases linearly with hematocrit. This dynamic lambdabt ratio has almost the same relationship to hematocrit as the static lambdabt ratio. By the use of appropriate hemotocrit-specific lambdabt values, we found that simultaneous blood flows calculated from the two indicators with different disappearance constants showed excellent agreement. If this hematocrit-dependent alteration in indicator partitioning is neglected, blood flow measurement in the dog with 133Xe washout may introduce an error of approximately 1.15% per unit hematocrit deviation from the normal value (taken as 45%), whereas blood flow measurements with 131I-iodanatipyrine washout had negligible errors.

Pharmacokinetics of benzene and toluene.

1. Experimental human exposure of benzene and toluene: Elimination curves obtained from a single exposure in which three male subjects inhaled 25 ppm of benzene and 100 ppm of toluene for 2 hrs were graphically resolved into a sum of three exponential components; for benzene in blood, $${\text{Y = }}5.93e^{ - 0.418t} + 8.60e^{ - 0.0238t} + 2.87e^{ - 0.00317t}$$ and for toluene in blood, $${\text{Y = 3}}5.5e^{ - 0.355t} + 35.2e^{ - 0.0197t} + 12.9e^{ - 0.00339t}$$ where Y is concentration in Μg/dl and t is time in minutes from 0 to 300. 2. Solubility of benzene and toluene in various body tissues of rabbits: The tissue-blood partition coefficients for the most body tissues were in the range of 1–3. On the other hand, the solvent vapors were extremely soluble in the fat, approximately 30–50 times as much as in the blood. 3. A mathematical analysis of the transfer of benzene and toluene in a living body: Using the results described in 2., a mathematical model with regard to the absorption, distribution, metabolism and elimination of the solvent was constructed. The model could offer a possible explanation for the three-exponential decay observed in the human experimental exposure.