Whole-body clearance

Whole body retention studies in mice, rats, monkeys, and dogs following intravenous injection of radiolabeled silver nitrate indicate that silver excretion in these species follows a triexponential profile (Furchner et al. 1968). For mice and monkeys, this differs from the biexponential profile seen following oral exposure. Whole body clearance following intravenous exposure was slower than clearance following oral exposure in each of the four species observed. In addition, the difference in clearance rate between species was more dramatic. Clearance at 2 days post-exposure ranged from 15% in the dog to 82% in the mouse (see Table 2-5) (Furchner et al. 1968). 

While distribution to tissues relies on the mechanism of plasma clearance, whole-body clearance is the result of metabolism and the excretion of low molecular-weight oligonucleotides. Ubiquitous nucleases are known to metabolize oligonu-... 

Norwich, K., Noncompartment models of whole-body clearance of tracers A review, Annals of Biomedical Engineering, Vol. 25, 1997, pp. 421-439. 

In the special steady-state case where the plasma concentration is constant but not zero (e.g./ as may happen when a large intraperitoneal infusion delivers sufficient mass to increase the plasma concentration to a level consistent with a mass balance between intraperitoneal delivery and whole-body clearance)/ a generalized form of Equation 9.5 applies — that is. 

In humans and mice, the excretion of organic mercury occurs largely by the fecal route, and follows first-order kinetics. The whole body clearance times and blood clearance periods are longer than those for inorganic mercury with the half-life of DMM being 78 days in humans. Other excretory routes are urine, sweat, and hair. 

The elimination of inorganic manganese from the human body is a two-phase process. The mean whole-body clearance halftime is about 4 days for the fast phase, and 39 days for the slow phase, during which about two-thirds of the elimination occurs. Results obtained with experimental animals showed the clearance half-time in the brain to be longer than that for the whole body (WHO 1981). 

A study of metabolism at the enzyme, sub-cellular or cellular level can be the basis, through scaling, to a prediction of whole body clearance... 

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). 

The terminator of drug action is, of course, elimination. Elimination is a composite of excretion (kidney, etc.) and biotransformation (metabolism). The primary measure of drug elimination from the whole body is clearance, CLt, defined as the volume of plasma fluid removed of drug per unit time. It is a direct measure of the loss of the drug from the system and can be calculated from Eq. (3.5) after IV administration of a dose of the drug. 

Holma, B. (1967). Lung clearance of mono- and di-disperse aerosols determined by profile scanning and whole body counting A study on normal and S02 exposed rabbits. Acta Med. Scand. (Suppl.) 473 1-102. 

The term clearance is used here in the sense of total body clearance and is analogous to the term renal clearance. The body as a whole is regarded as acting as a xenobiotic-eliminating system, where the rate of elimination divided by the average plasma concentration of the compound is the total body clearance. Here clearance is calculated (25) by dividing the administered dose of the substance by the area under the plasma concentrationtime curve produced by that dose. This pharmacokinetic parameter, as well as others presented in this publication, was calculated by the use of the MLAB on-line computer system established at the National Institutes of Health by Knott and Reece (26). Similar to t the total clearance is a composite of the individual clearances of the material by the various tissues of the body. 

The retention of selected isotopes by amphibians and reptiles is quite variable. For example, whole-body retention of after intraperitoneal injection in the rough-skinned newt showed two distinct loss components with biological half-lives of 2 and 210 days. The slower component accounted for 26% of the administered activity thyroid contained 78% of the total and clearly accounted for the long-term component (Willis and Valett 1971). However, similar studies with 1 and the leopard frog showed three distinct loss components (0.1 day 1.4 to 2.9 days 44.3 to 69.4 days) loss of each component was greater at 25°C than at 10°C. Also, the fast component probably represented plasma clearance through urinary excretion (Willis and Valett 1971). 

I]ITU has been applied in clinical trials for distribution and clearance studies, [123I]ITU for the whole body imaging studies and [131I]ITU to successfully treat the Harding-Passey melanoma carried in Balb/c mice369. 

The distribution of chromium(III) in humans was analyzed using a whole-body scintillation scanner, whole-body counter, and plasma counting. Six individuals given an intravenous injection of 51chromium(III) as chromium trichloride had >50% of the blood plasma chromium(ni) distributed to various body organs within hours of administration. The liver and spleen contained the highest levels. After 3 months, the liver contained half of the total body burden of chromium. The study results indicated a three-compartment model for whole-body accumulation and clearance of chromium(III). The half-lives were 0.5-12 hours for the fast component, 1-14 days for the medium component, and 3-12 months for the slow component (Lim et al. 1983). 

Because clearance at the whole-body level often is determined by metabolism at the cellular level, it is possible to use a variety of human-derived in vitro systems to determine rates of metabolism. These systems include pure human enzymes (such as cytochrome P450 enzymes) (13) and human liver subcellular fractions (S9 and microsomes) (14). However, with enzymes and subcellular fractions, some information is lost because the whole-cell integration of subcellular processes has been disrupted. The use of cultured human hepatocytes retains the whole-cell integration at the expense of greater experimental complexity (15). Each system provides a different window on the metabolic processes, is relatively easy to use, and can be obtained from commercial sources. Rates and pathways of metabolism may be compared with a series of discovery compounds to identify those with the greatest relative metabolic stability or with a benchmark compound of known human PK characteristics to provide a more absolute estimate of hepatic metabolic clearance. 

Steady-slate concentration was reached rapidly. The 90% steady-state concentrations were reached after 2.2. 5.2 and 4.2 days, for edible, nonediblc and whole body compartments, respectively. Depuration of residues also occurred rapidly when tile tish were placed in dean water. The 50% clearance levels of PBO in edible and nonedihle tissues and whole fish were 0.67, 1.6 and 1.3 days, respectively, Even under this extreme scenario of continuous exposure for 28 days, the BCFs were well below lOOOx and depuration was relatively rapid, i.e. 90% clearance within a few days. 

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