Perfused organs

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

Blood flow to various tissues or organs (e.g., well-perfused organs usually tend to accumulate more chemical than less well perfused organs). 

The kidneys are extremely well-perfused organs, with about 1500 L of blood flowing through them every day. Approximately 180 L of primary urine is filtered out of this. Removal of water leads to extreme concentration of the primary urine (to approximately one-hundredth of the initial volume). As a result, only a volume of 0.5-2.0 L of final urine is excreted per day. 

The initial unequal tissue-drug distribution cannot persist, however, because physicochemical forces tend to require an eventual establishment of concentration equilibria with other less well perfused organs. Therefore, as the drug continues to be removed from the blood by the less richly perfused tissues or eliminated by metabolism and excretion or both, plasma levels will fall, and the concentration of anesthetic in the brain will decline precipitously. 

The decomposition of nitric oxide in oxygenated perfused organ baths is commonly assumed to occur by the third-order reaction of... 

The amide local anesthetics are widely distributed after intravenous bolus administration. There is also evidence that sequestration can occur in lipophilic storage sites (eg, fat). After an initial rapid distribution phase, which consists of uptake into highly perfused organs such as the brain, liver, kidney, and heart, a slower distribution phase occurs with uptake into moderately well-perfused tissues, such as muscle and the gastrointestinal tract. As a result of the extremely short plasma half-lives of the ester type agents, their tissue distribution has not been extensively studied. 

The one-compartment model of distribution assumes that an administered drug is homogeneously distributed throughout the tissue fluids of the body. For instance, ethyl alcohol distributes uniformly throughout the body, and therefore any body fluid may be used to assess its concentration. The two-compartment model of distribution involves two or multiple central or peripheral compartments. The central compartment includes the blood and extracellular fluid volumes of the highly perfused organs (i.e., the brain, heart, liver, and kidney, which receive three fourths of the cardiac output) the peripheral compartment consists of relatively less perfused tissues such as muscle, skin, and fat deposits. When distributive equilibrium has occurred completely, the concentration of drug in the body will be uniform. 

After IV application, peptides and proteins usually follow a biexponential plasma concentration-time profile that can best be described by a two-compart-ment pharmacokinetic model [13]. The central compartment in this model represents primarily the vascular space and the interstitial space of well-perfused organs with permeable capillary walls, especially fiver and kidneys, while the peripheral compartment comprises the interstitial space of poorly perfused tissues such as skin and (inactive) muscle [4]. 

Intact Animal, Perfused Organ, Cells, or Subcellular Fraction Drug-Metabolising capability Determining Mutagenic Frequency ... 

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. 

Whereas sophisticated studies require the technology to be available in-house in preparation e.g. of slices or performing an organ perfusion study (see also chapter on Perfused Organs), others can be performed with cells (Li 1999) or fractions commercially available or easily prepared. A typical preparation scheme for preparation of subcellular fractions by differential centrifugation is given in Figure 3. 

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... 

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