Tissue compartments

HIV-1 infection results in dissemination of the virus to different cellular and tissue compartments. Some of these anatomical sanctuaries, for example the genital tract (Bym and Kiessling 1998) and the CNS (Kravcik et al. 1999 Rolinski et al. 1997),... 

PBPK models have also been used to explain the rate of excretion of inhaled trichloroethylene and its major metabolites (Bogen 1988 Fisher et al. 1989, 1990, 1991 Ikeda et al. 1972 Ramsey and Anderson 1984 Sato et al. 1977). One model was based on the results of trichloroethylene inhalation studies using volunteers who inhaled 100 ppm trichloroethylene for 4 horns (Sato et al. 1977). The model used first-order kinetics to describe the major metabolic pathways for trichloroethylene in vessel-rich tissues (brain, liver, kidney), low perfused muscle tissue, and poorly perfused fat tissue and assumed that the compartments were at equilibrium. A value of 104 L/hour for whole-body metabolic clearance of trichloroethylene was predicted. Another PBPK model was developed to fit human metabolism data to urinary metabolites measured in chronically exposed workers (Bogen 1988). This model assumed that pulmonary uptake is continuous, so that the alveolar concentration is in equilibrium with that in the blood and all tissue compartments, and was an expansion of a model developed to predict the behavior of styrene (another volatile organic compound) in four tissue groups (Ramsey and Andersen 1984). 

Durbin and Schmidt (1985) proposed a model for tissue distribution and excretion of absorbed americium in humans. A unique feature of this model is that transfers from plasma to tissues are assumed to be instantaneous therefore, a central plasma (and blood) compartment is not included in the model (see Figure 3-10). Tissue compartments included in the model are slow and fast turnover bone compartments, representing cortical and trabecular bone, respectively liver and slow and fast turnover for other soft tissue compartments. Excretion pathways include urine and feces. Urinary excretion is represented as a sum of the contributions from bone, liver, and other soft tissues. Fecal americium is assumed to be excreted from the liver. 

Figure 2A illustrates a noneliminating tissue compartment, i, divided into three anatomically relevant subcompartments, each homogeneous with respect to drug concentration. The corresponding differential mass balance equations are... 

Drug elimination from a membrane-limited tissue compartment requires subtraction of the rate of elimination, qh from the appropriate mass balance equation, typically from subcompartment 2. 

Lumping compartments 1, 2, and 3 into a single homogeneous tissue compartment implies the blood flow-limited model. The tissue mass balance equation for a noneliminating organ is... 

A complete or global tissue distribution model consists of individual tissue compartments connected by the blood circulation. In any global model, individual tissues may be blood flow-limited, membrane-limited, or more complicated structures. The venous and arterial blood circulations can be connected in a number of ways depending on whether separate venous and arterial blood compartments are used or whether right and left heart compartments are separated. The two most common methods are illustrated in Figure 3 for blood flow-limited tissue compartments. The associated mass balance equations for Figure 3A are... 

A modification of the forcing function approach makes use of linear systems analysis for individual tissue compartments [59], Parametric or nonparamet-ric functions are fitted to observed blood drug concentration-time data and are then combined with tissue drug concentration-time measurements deconvolved... 

Absorbed lead is distributed in various tissue compartments. Several models of lead pharmacokinetics have been proposed to characterize such parameters as intercompartmental lead exchange rates, retention of lead in various pools, and relative rates of distribution among the tissue groups. See Section 2.3.5 for a discussion of the classical compartmental models and physiologically based pharmacokinetic models (PBPK) developed for lead risk assessments. 

Target tissues. Output from the O Flaherty Model is an estimate of age-specific blood lead concentrations. The O Flaherty Model has also been used to predict lead concentrations in bone and other tissue compartments (O Flaherty 1995a), in order to evaluate correspondence between predicted tissue concentrations and observed concentrations in different populations of children and adults. 

Unidirectional, first-order transfer rates (day1) between compartments were developed for 6 age groups, and intermediate age-specific values are obtained by linear interpolation. The range of age-specific transfer rate values are given in Table 2-8. The total transfer rate from diffusible plasma to all destinations combined is assumed to be 2,000 day"1, based on isotope tracer studies in humans receiving lead via injection or inhalation. Values for transfer rates in various tissues and tissue compartments are based on measured deposition fractions, or instantaneous fractional outflows of lead between tissue compartments (Leggett 1993). 

Target tissues. The output from the Leggett Model is an estimate of age-specific PbB concentrations. The current version of the Leggett Model does not save as output the interim parameter values determined for lead in other tissues or tissue compartments. 

The multimedia model present in the 2 FUN tool was developed based on an extensive comparison and evaluation of some of the previously discussed multimedia models, such as CalTOX, Simplebox, XtraFOOD, etc. The multimedia model comprises several environmental modules, i.e. air, fresh water, soil/ground water, several crops and animal (cow and milk). It is used to simulate chemical distribution in the environmental modules, taking into account the manifold links between them. The PBPK models were developed to simulate the body burden of toxic chemicals throughout the entire human lifespan, integrating the evolution of the physiology and anatomy from childhood to advanced age. That model is based on a detailed description of the body anatomy and includes a substantial number of tissue compartments to enable detailed analysis of toxicokinetics for diverse chemicals that induce multiple effects in different target tissues. The key input parameters used in both models were given in the form of probability density function (PDF) to allow for the exhaustive probabilistic analysis and sensitivity analysis in terms of simulation outcomes [71]. 

Baker et al. [137] reported that Rhesus monkeys were administered primaquine (6-10.5 mg as the phosphate/kg intravenously) and plasma samples were analyzed by high performance liquid chromatography for the presence of the unchanged drug and the major metabolite, 8-[3-carboxy-l-methylpropylamino)-6-methoxyquinoline. Primaquine had an unusually high affinity for tissue compartments, which produced a rapid initial drop in plasma concentration. Within 15 min, the plasma concentration of the metabolite far exceeded that of primaquine. Thirty-five to eighty-three percent of the primaquine dose was converted to the major metabolite. This metabolite possessed much lower affinity for the tissues compartments than the drug itself. 

Tanji N, Ross MD, Cara A, et al. Effect of tissue processing on the ability to recover nucleic acid from specific renal tissue compartments by laser capture microdissection. Exp. Nephrol. 2001 9 229-234. 

Magdalena, A.B., et al., Food safety implications of the distribution of azaspiracids in the tissue compartments of scallops (Pecten maximus). Food Addit. Contam., 20, 2, 154, 2003b. 

Diffusion is defined as the random translational motion of molecules or ions that is driven by internal thermal energy - the so-called Brownian motion. The mean movement of a water molecule due to diffusion amounts to several tenth of micrometres during 100 ms. Magnetic resonance is capable of monitoring the diffusion processes of molecules and therefore reveals information about microscopic tissue compartments and structural anisotropy. Especially in stroke patients diffusion sensitive imaging has been reported to be a powerful tool for an improved characterization of ischemic tissue. 

In addition, spectroscopic techniques have been applied for assessment of diffusion properties (e.g., Refs. 52-56). Changes in the diffusion of water molecules and further metabolites reveal pathological alterations of tissue compartments not visualized by other modalities. Information about cellular tissue architecture under normal and pathological conditions can be provided. 

Figure 7-2 illustrates a three-compartment structure assumed by McJilton et al. for describing radial diffusion. It consisted of a gas phase in the lumen of the airway, a liquid layer that lined the airway, and a tissue compartment. The rate of movement of the gas into the liquid layer, dm /dt is a function of the solubility of the gas in the liquid, as defined by the Henry s law constant. The rate of movement of the gas molecules across the liquid layer to the tissue compartment, dm /dt is a function of the diffusion co cient of the gas in the mucus and serous... 

Physiologically Based Toxicokinetic (PBTK) models are derived similarly to Physiologically Based Pharmacokinetic (PBPK) models, which have been used for a number of years in the development of medicinal drugs. They describe the rat or man as a set of tissue compartments, i.e., liver, adipose tissues, poorly perfused tissues, and richly perfused tissues along with a description of metabolism in the liver. In case of volatile organic compounds a description of gas exchange at the level of the lung is included, see also Section 4.3.6. 

If we now plot the same data points, but this time take the logarithm of the plasma concentration, tlie curved line of Fig. 6a becomes a straight line (Fig. 6b), and we can start to use it to derive some useful information. First of all, let us think of the body as a single, big compartment. What volume does this compartment have If the 100 mg of drug we have injected intravenously were to be distributed instantaneously through not only the vascular compartment but also any other tissue compartments it is able to enter, it would be a bit like putting the drug... 

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