Liver concentration

Tissue Soft tissue liver concentration ratiob (number of mixed exposures) ... 

The Leggett Model simulates lead biokinetics in liver with two compartments the first simulates rapid uptake of lead from plasma and a relatively short removal half-life (days) for transfers to plasma and to the small intestine by biliary secretion a second compartment simulates a more gradual transfer to plasma of approximately 10% of lead uptake in liver. Different transfer rates associated with each compartment are calibrated to reproduce patterns of uptake and retention of lead observed in humans, baboons, and beagles following intravenous injection, as well as blood-to-liver concentration ratios from data on chronically exposed humans. Similarly, the Leggett Model simulates lead biokinetics in three compartments of soft tissues, representing rapid, intermediate, and slow turnover rates (without specific physiologic correlates). 

After 5 weeks, fish from the most heavily contaminated site (2100 mg total PCBs/kg DW sediment) had liver concentrations of non-ortho (PCBs 77, 126, 169) plus mono-ortho PCBs of 29.3 mg/kg DW, reduced growth, and 30% mortality. Progeny of fish from this group had significantly reduced survival and a greater incidence of spinal abnormalities when compared to fish from a reference site... 

The steady-state liver concentrations of chlordecone were similar in male and female rats and mice at each of the doses. These levels may, therefore, be important for interspecies comparisons since chlordecone is not metabolized in rats but is metabolized in humans. 

Burbot, a bottom-feeding fish, taken from remote lakes in Canada in 1985--1986, contained liver concentrations of mirex ranging between 3.7 and 17.4 pg/kg (ppb) lipid weight (detection limit, 0.5 p g/kg), while photomirex was not detected. The lowest mirex values were seen in fish from the most remote locations, suggesting that atmospheric transport of this compound was occurring (Muir et al. 1990). 

Microdialysis sampling has been used in rats infused with phenol (0.181 nmol/minute for 90 minutes) to study excretion into the bile (Scott and Lunte 1993). For all phenol metabolites, bile concentrations were higher than liver concentrations indicating that the metabolites are actively excreted in the bile. 

Nashelsky et al. (1995) described one non-fatal assault and three deaths in which chloroform was utilized. Blood and/or tissue concentrations of chloroform were determined in the assault victim and one decedent within 24 hours, within 10 days in another decedent who was frozen for the majority of that period, and after 5 months without preservation in the last decedent. Blood concentrations in 2 decedents were 2 and 3 pg/mL fat concentrations were 10 and 42 pg/mL brain concentrations were 3 and 46 pg/mL and the liver concentration in one decedent was 24 pg/mL. Due to the nature of the tissues analyzed, these data should be regarded as qualitative indicators of chloroform absorption only. 

In animal studies, the tissue distribution of " C-1,4-dichlorobenzene in female CFY rats was found to be similar following inhalation, oral, and subcutaneous exposure (Hawkins et al. 1980). The inhalation exposure regimen was 10 consecutive days of exposure to " C-1,4-dichlorobenzene at 1,000 ppm for 3 hours per day, and the highest concentrations of " C were measured in fat (up to 557 g/g via inhalation) and next highest levels in kidneys and liver. Concentrations in kidney and liver were about 5-10% of that found in adipose tissue, irrespective of the route of exposure. Distribution patterns for all routes were also similar to those observed by Kimura et al. (1979) using the oral route, as described below. 

Viluksela M et al Subchronic/chronic toxicity of a mixture of four chlorinated dibenzo- -dioxins in rats. I. Design, general observations, hematology, and liver concentrations. Toxicol Appl Pharmacol 151 57, 1998... 

To make quantitative predictions of DDI for the new compound as perpetrator, a reliable estimate of a relevant in vivo concentration is needed. What is tmly needed is knowledge of the concentration of the inhibitor available to bind to the enzyme. For liver, if the well accepted free-dmg hypothesis (which underwrites fundamental drug action principles in pharmacology) is applied for DDI, then the use of a free intracellular liver concentration is needed. For inhibitors that are permeable through membranes, the free concentration in the portal vein should serve as the closest proxy for free intracellular concentration in the liver. Diminished permeability as well as active uptake and efflux from liver cells can confound this relationship. Nevertheless, use of estimates of unbound portal vein concentrations (which can be estimated from... 

Chloroquine reaches high liver concentrations and may be used for amebic abscesses that fail initial therapy with metronidazole... 

Other compounds cause liver necrosis because of biliary excretion. Thus, the drug furosemide causes a dose-dependent centrilobular necrosis in mice. The liver is a target as a result of its capacity for metabolic activation and because furosemide is excreted into the bile by an active process, which is saturated after high doses. The liver concentration of furosemide therefore rises disproportionately (chap. 3, Fig. 34), and metabolic activation allows the production of a toxic metabolite (Fig. 6.6). The drug proxicromil (chap. 5, Fig. 11) caused hepatic damage in dogs as a result of saturation of biliary excretion and a consequent increase in hepatic exposure. 

Fig. 4.6 Correlation of plasma trough concentrations (24 h post dose) with liver concentrations of ISIS 113715 after 3 months administration (1 to 10 mg/kg administered once weekly, via a 1 -h IV infusion).

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