Isolated perfused lung model

Longmore WJ (1982) The isolated perfused lung as a model for studies of lung metabolism. In Farrel PM (ed.) Lung Development Biological and Clinical Perspectives. Academic Press Inc, New York, pp 101-110. 

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. 

Linder A, Friedel G, Fritz P, Kivisto KT, McClellan M, Toomes H (1996) The ex-vivo isolated, perfused human lung model description and potential applications. Thorac Cardiovasc Surg 44 140-146. 

Nyhlen K, Rippe B, Hultkvist-Bengtsson U (1997) An isolated blood-perfused guinea-pig lung model for simultaneous registration of haemodunamic, microvas-cular and respiratory variables. Acta Physiol Scand 159 293-302. 

Ryrfeldt A, Persson G, Nilsson E (1989) Pulmonary disposition of the potent glucocorticoid budesonide, evaluated in an isolated and perfused rat lung model. Biochem Pharmacol 38 17-22. 

Saldias FJ, Cornelias A, Guerrero C, Ridge KM, Rutschman DH, Sznajder JI (1998) Time course of active and passive liquid and solute movement in the isolated perfused rat lung model. J Appl Physiol 85 1572-1577... 

Quercetin has been found to inhibit P-gp-mediated efflux of ritonavir in Caco-2 cells (47), to reduce the oxidation of acetaminophen in rat liver microsomes and HepG2 cells (48), and to inhibit the metabolism of midazolam and quinidine in human liver microsomes (49). It did not have an effect on CYP3A4-mediated metabolism and P-gp-mediated transport of saquinavir (41). Rutin was demonstrated to moderately increase the uptake of idar-ubicin in an isolated perfused rat lung model, and also the outflow recovery of the major metabolite idarubicinol, possibly by affecting P-gp (45). Nobe-litin and tangeretin were shown to inhibit OATP-B-mediated uptake of estrone-3-sulfate into human embryonic kidney cells (23). 

In 1996, Sciuto and coworkers showed that intratracheal administration of DBcAMP reduced oedema formation in an isolated, perfused rabbit lung model (Sciuto et al., 1996b). Again, LTC4, D4 and E4 production was inhibited. It was noted that intratracheal administration of DBcAMP was more effective than intravascular administration. 

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. 

In human as well as in some experimental models, such as the canine (Mentzer et al. 1975) and feline (Neely et al. 1989), adenosine has been demonstrated to act as a vasodilator in the lungs during conditions of elevated tone. However, the contribution of A3AR to this effect is not clear. Earlier studies have postulated A2 receptors to mediate adenosine-induced vasodilatation (Berne 1963 Phillis et al. 1987 McCormack et al. 1989). In the pulmonary circulation of rabbits and rats, adenosine has been reported to produce vasodilation via A2aAR or A2BAR, respectively (El-Kashef et al. 1999 Haynes et al. 1995,1999). Accordingly, in an isolated blood-perfused rat lung, adenosine-induced vasodilatation was shown to be... 

Earlier we described how pharmacokinetic and dynamic properties of inhaled drugs are relevant for pulmonary selectivity. The assessment of pharmacokinetic and dynamic properties is consequently relevant for drug development and clinical practice. This section reviews some of the relevant techniques for assessing such properties. The available tools range from cell culture or isolated lung perfusion models to mucociliary clearance analysis, imaging techniques, and in vivo pharmacokinetic and dynamic analysis of the inhaled drug. 

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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