Animal models lead absorption

Historically, drug absorption, distribution, metabolism, excretion, and toxicity ADMET) studies in animal models were performed after the identification of a lead compound. In order to avoid costs, nowadays pharmaceutical companies evaluate the ADMET profiles of potential leads at an earlier stage of the development... 

HFE has been shown to be located in cells in the crypts of the small intestine, the site of iron absorption. There is evidence that it associates with P2 niicroglobu-lin, an association that may be necessary for its stability, intracellular processing, and cell surface expression. The complex interacts with the transferrin receptor (TfR) how this leads to excessive storage of iron when HFE is altered by mutation is under close smdy. The mouse homolog of HFE has been knocked out, resulting in a potentially useful animal model of hemochromatosis. 

Adult subjects who ingested soil (particle size less than 250 im) from the Bunker Hill NPL site absorbed 26% of the resulting 250 pg/70 kg body weight lead dose when the soil was ingested in the fasted state and 2.5% when the same soil lead dose was ingested with a meal (Maddaloni et al. 1998). There are no reported measurements of the absorption of soil-bome lead in infants or children. Additional evidence for a lower absorption of soil-bome lead compared to dissolved lead is provided from studies in laboratory animal models. In immature swine that received oral doses of soil from one of four NPL sites (75 or 225 ig Pb/kg body weight), bioavailability of soil-bome lead ranged from 50% to 82% of that of a similar... 

Pharmacokinetics, which normally include bioanalytical chemistry, to assess the absorption or delivery and disposition profiles of the leads in animal models using the route of administration projected for clinical studies and drug metabolism using in vitro systems to assess the extent of metabolism by the various drug metabolism enzymes... 

The absorption of essential metals from the intestinal contents into the blood is under feedback control, such that deficiencies in metals can enhance their uptake from the intestine. Unfortunately, this can have adverse consequences relative to metal uptake in individuals with dietary imbalances. For example, it has been reported that iron deficiency in malnourished children is associated with increased blood lead concentration. In animal models (e.g., rats) it has been shown that iron deficiency increases the gastrointestinal uptake of lead, perhaps due to an increase in the number of iron-transport proteins. In the absence of iron, the transport proteins may be... 

In the specific case of lead metabolism, a number of models have been proposed and published over the years to rationalize the biological behaviour of lead in human subjects and experimental animals. The development and predictive utility of these models rest in large part on the considerable amount of empirical information available in the literature, relating to lead absorption, distribution, excretion, and retention in humans and test species. 

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR), a chloride (CF) channel characterised by chloride permeability and secretion, and also by the regulation of other epithelial ion channels (Eidelman et al, 2001). Mutations in the CFTR gene lead to an impaired or absent Cl conductance in the epithelial apical membrane, which leads to defective Cl secretion and absorption across the epithelium. Genistein (Illek et al, 1995 Weinreich et al, 1997) and other flavonoids (Illek and Fisher, 1998) have been shown, in different animal and tissue models, to activate wild-type CFTR and CFTR mutants by (Eidelman et al, 2001 Roomans, 2001 Suaud et al, 2002) ... 

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