Perfused organ system

Traditionally, drug metabolism studies have relied on the use of model systems to predict metabolic pathways in human. For this purpose, either in vivo whole animal system (utilizing small laboratory animal models) or in vitro enzyme systems (microsomal preparations, tissue cultures or perfused organ systems) have been widely employed [14, 15]. In biomedical research, animal systems continue to serve an important role as models for biological responses in man. 

The introduction of in vitro techniques (microsomal preparations, tissue cultures, perfused organ systems, or purified enzymes) was meant to overcome many of those problems unique to whole animals systems. Because liver is the major site of chemical and drug biotransformation, it is the tissue of choice for metabolism and toxicity studies, the majority of which are conducted using microsomal preparations [16]. While there is considerable impetus to perform metabolism studies using this technique, they may be complicated by several commonly encountered practical problems, including [13] ... 

Gas or hquid chromatography MS and NMR ( H/ C) are the most common experimental approaches employed in investigations of pathway flux analysis. These approaehes, when coupled with the application of stable isotope traeers in whole animals, isolated perfused organ systems and cell culture, have allowed researchers to disseet the dynamic processes tmderlying dietary organic nutrient... 

In the early phase of serious intraabdominal infections, attention should be given to preserving major organ system function. With generalized peritonitis, large volumes of intravenous (IV) fluids are required to maintain intravascular volume, to improve cardiovascular function, and to ensure adequate tissue perfusion and oxygenation. Adequate urine output should be maintained to ensure appropriate fluid resuscitation and to preserve renal function. A common cause of early death is hypovolemic shock caused by inadequate intravascular volume expansion and tissue perfusion. 

Studies on in vitro systems of various kinds (including whole perfused organs, tissue slices, cell, tissue and organotypic cultures, and sub cellular fractions). 

Traditionally, drug metabolism studies rely on the use of model systems to predict the intermediates and products of dmg metabolism in humans. For these purposes whole animal systems are in use, especially small laboratory animal models (e.g. rat, dog, cat, guinea pig, rabbit). In vitro studies are generally used to complement and specify the data obtained using perfused organs, tissue or cell cultures, and microsomal preparations. As discussed in more detail later, microorganisms can be used as model systems as well. 

Perfused organs Phase I and II present, whole metabolic profile observed, best correlation to in vivo expensive, ex vivo animal trial, complex methodology, high technical effort, batch variability, more complicated than enzyme-only system, quality control, limited use for multiple compounds... 

This raises the question of what in vitro system to use and which system wiii provide reai data on the reiative rates of metaboiism in different species. Shouid tissue siices, isoiated ceiis, homogenates, or subceiiuiar fractions be used One approach to this difficuity is to use the rate of metaboUsm per gram of tissue (or mg protein) derived from the perfused organ studies in rat as the yardstick by which to vaiidate the rate of metaboiism in in vitro systems. Often the rate of metaboiism in siices, isoiated ceiis, homogenates, or subceiiuiar fractions with an arbitrary incubation medium is weii beiow the expected iev-eis. However, by judicious manipuiation of the incubation medium, it shouid be possibie to improve the nature and rates of metaboiism in vitro so that the rates approach the whoie perfused organ. If the improved rates are 80% or more than that in the whole organ, then cross-species comparisons that use the same conditions should provide data that can be used for go/no-go decisions. 

Many Experimental Units. An important advantage of hepatocytes both over the intact animal, and perfused organ, is that cells isolated from one liver or liver sample can be divided over a large number of experimental units. This is very useful for studying e.g. dose- and time- relationships in the biotransformation or toxic effects of a compound, or for comparing the effects of different compounds, and studying the interactions between a number of compounds. The fact that the system is easy to handle and small in volume, makes it very suitable for the use of radiolabeled or rare and expensive compounds. 

Isolated or Perfused Organ Whole Cells Cell-Free Systems Purified Components... 

At present a wide range of isolated organ systems is available. The use of isolated and perfused organs, such as the intestine, to study ADME in vitro has been reported to be highly predictive of the in vivo situation, including absorption at the organ level [55, 60]. 

Various studies have addressed the antioxidant capacity of Pycnogenol in simplified assay systems in vitro, cultured cell models, perfused organs, and in vivo. Blazso and coworkers tested the in vitro scavenging activity of Pycnogenol as well as three... 

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