Fed states

Digestive enzymes of the gastrointestinal tract begin hydrolysis of protein, fat, and carbohydrates into their component building blocks, namely, amino acids, fatty acids and monoacylglycerols, and simple sugars (such as glucose). 

Intestinal epithelial cells take up these compounds, process them further, and then release them into the hepatic portal circulation. 

Increased blood levels of these nutrients, especially glucose and amino acids, stimulate the pancreas to release insulin and suppress glucagon release. 

The liver is the first organ to respond to the influx of nutrients after a meal. 

The hepatic portal vein carries the nutrients directly to the liver. 

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Acetyl-CoA carboxylase is an allosteric enzyme and is activated by citrate, which increases in concentration in the well-fed state and is an indicator of a plentiful supply of acetyl-CoA. Citrate converts the enzyme from an inactive dimer to an active polymeric form, having a molecular mass of several milhon. Inactivation is promoted by phosphorylation of the enzyme and by long-chain acyl-CoA molecules, an example of negative feedback inhibition by a product of a reaction. Thus, if acyl-CoA accumulates because it is not esterified quickly enough or because of increased lipolysis or an influx of free fatty acids into the tissue, it will automatically reduce the synthesis of new fatty acid. Acyl-CoA may also inhibit the mitochondrial tricarboxylate transporter, thus preventing activation of the enzyme by egress of citrate from the mitochondria into the cytosol. 

In the Fed State, Metabolic Fuel Reserves Are Laid Down... 

Under normal feeding patterns the rate of tissue protein catabolism is more or less constant throughout the day it is only in cachexia that there is an increased rate of protein catabolism. There is net protein catabolism in the postabsorptive phase of the feeding cycle and net protein synthesis in the absorptive phase, when the rate of synthesis increases by about 20-25%. The increased rate of protein synthesis is, again, a response to insulin action. Protein synthesis is an energy-expensive process, accounting for up to almost 20% of energy expenditure in the fed state, when there is an ample supply of amino acids from the diet, but under 9% in the starved state. 

The properties of the human GIT that are relevant to the absorption of drug products have been collected from several sources [62-69]. Figure 2.3 shows a cartoon of the GIT, indicating surface area and pH (fasted and fed state) in the various... 

Surfactants added to dissolution media of insoluble drugs may produce dissolution results which are more indicative of the in vivo fed state than of the fasted state. 

As noted earlier, osmotic systems have been shown to provide good in vitro-in vivo correlations between the observed release rates. This has been shown explicitly for the core I devices described above [33], The data are shown in Figure 16, where the in vitro data are plotted along with the release curves from six devices administered to dogs. The animals were in the fed state at the time of administration and maintained that way throughout the duration of the experiment via the administration of —50 g of dog chow before device administration and every hour thereafter. The individual release curves shown in Figure 16 were obtained by numerical deconvolution of the plasma data with an oral solution dose given to the same dog. Clearly the in vivo and in vitro data are... 

Tab. 21.1. Summary of physiological gastrointestinal characteristics in fasted and fed state of importance for drug dissolution and solubility.

For highly permeable, poorly soluble drugs given in lower doses, the dissolution rate rather than the saturation solubility is the limiting factor. An increase in dissolution rate due to in vivo solubilization mediated by food intake could theoretically be obtained, but this situation is not always found in vivo. For example, food does not affect the rate and extent of bioavailability for candesartan cilexitil, a very poorly soluble compound [78], An in vitro dissolution and solubility study of this compound in simulated intestinal media provided a potential explanation it was revealed that the solubility was increased as a function of bile concentration as expected, whereas the dissolution rate was not increased by the higher bile concentrations being representative for the fed state (see Fig. 21.14). Thus, although... 

Cowles VE, Sarna SK Trichinella spiralis infection alters small bowel motor activity in the fed state. Gastroenterology 1991,101 664-669. 

In the GI tract, different hydrodynamic conditions are present, depending on the fasted or the fed state. Contraction patterns are controlled in terms of electromechanical impulses (myoelectric activity) as well as by various hormones (cholecystokinin, secretin, glucagon, motilin, and insulin, for example). In the fasted state, the motility pattern is regulated by the (interdigestive) migrating myoelectric complex [(I)... 

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