Organ perfusion Lung model

Lung cell cultures can provide mechanistic insights but they do not represent the complexity in the delivery and disposition of drugs in the human respiratory tract. Perfused lung organ studies provide the next level in complexity. Various animal models have been used with the view to predict quantitatively absorption of peptides and proteins from the human lungs. However, due to the major differences in the anatomy and physiology of respiration in primates, the predictive power of these models is quite limited as evidenced by the data in Fig. 2. (Animal models are, of course, essential in the assessment of safety and they can provide valuable mechanistic information.)... 

In addition to cell-based models, tissue-based models such as the Ussing chamber technique, the everted gut sac approach, and perfused isolated intestinal segments are also used, but only when it is important to understand the absorption processes in more detail. Unlike Caco-2, tissue-based models have the correct physiological levels of transporters and the presence of an apical mucus layer. Also, in situ and isolated organ perfusion methods exist for the gut, liver, lungs, kidneys, and brain and can provide data not directly obtainable in vitro. The isolated perfused liver is particularly useful since it allows an assessment of first-pass hepatic clearance, the quantitative distribution of metabolites in liver, blood, and bile, the effects of binding to plasma proteins and intracellular sites, and cellular uptake processes. 

French MC, Wishart GN (1985) Isolated perfused rabbit lung as a model to study the absorption of organic aerosols. J Pharmacol Methods 13 241-248. 

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. 

The tissue compartments included in the Johanson model are as follows the lungs, presumed to be the only site of uptake, and arterial blood the liver, presumed to be the only organ where transformation of 2-butoxyethanol takes place the gastrointestinal tract in equilibrium with the liver a group of richly perfused tissues a group of poorly perfused tissues a fat compartment and muscles and skin. Support... 

Isolated lung, liver, and kidney perfusions have been recognized for decades as important models for toxicology and pharmacology. Part of their acceptance relates to the ease of harvest because these organs are anatomically structured with closed vascular systems containing easily identifiable arterial inputs and venous outputs, both amenable to catheterizations with minimal expertise in surgery. In contrast, outside the possible exception of ears, skin does not possess such a closed vascular system. 

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