Absorption transcellular

PAMPA is typically used to make a prediction of the passive, transcellular absorption of a compound. Compounds which may be absorbed by a paracellular mechanism or may be substrates for active transport (uptake or efflux) are usually better assessed in a cell based system. A combination of assays can be applied to gain a greater understanding of the permeability and transport properties of a compound. 

All these compounds are moderately lipophilic and should show excellent ability to cross biological membranes by transcellular absorption. Propranolol, betaxolol and metoprolol all have minimal gut first-pass metabolism, as shown by the low value for E(g. i.). Metabolism and first pass effects for these compounds are largely confirmed to the liver as shown by the values for E(g. i.). In contrast talinolol shows high extraction by the gastrointestinal tract with low liver extraction [13]. These effects are illustrated graphically in Figure 3.9 which shows the bioavailability predicted from hepatic extraction contrasted with that seen in vivo in man. 

FIGURE 1.11 A scheme of the various absorption routes across the intestinal epithelium and cellular barriers to xenobiotics absorption. A, Transcellular absorption (plain diffusion) B, paracellular absorption C, carrier-mediated transcellular absorption D, facilitated diffusion E, the MDR and P-gp absorption barrier and F, endocytosis. (From Hunter, J. and Hirst, B.H., Adv. Drug Deliv. Rev., 25, 129, 1997. With permission.)... 

Several experiments have demonstrated that a correlation exists between log P and the degree of transcellular absorption of a homologous series of compounds. However, for structurally different compounds, such correlation could not be shown. The liposome partitioning system is employed increasingly as an alternative to the octanol approach (13, 14). 

Drugs can cross the intestinal epithelial barrier in a number of ways. They may permeate either through the cell (transcellular) or between adjacent cells (para-cellular). Enterocytes have tight intercellular junctions that restrict paracellular transport to small hydrophilic molecules.7 These cells possess active and facilita-tive transporters for nutrients, as well as an array of efflux transporters [e.g., P-glycoprotein (P-gp) and related transporters] and enzymes (e.g., cytochrome P450 type 3A4) that restrict transcellular absorption. Transcytotic transport of macromolecules is possible, but compounds are often destroyed in lysosomes. With the exception of M-cells, transcytosis is not considered a major mechanism of the transcellular pathway for absorption of macromolecules across gastrointestinal epithelium.6... 

Immobilized artificial membranes (lAM) are solid membrane mimetics that are covalently bound to the surface of a silica chromatographic support to generate a phospholipid monolayer. lAM chromatography can be applied to measure membrane partitioning of a given compound or to predict bile salt-membrane interactions they may also be used in studies on transcellular absorption. Artificial membranes appear to be well correlated with 1-octanol/water partition coefficients however, since the latter can be well predicted in silico, the real value of AIMs is the ability to study complex molecules or extracts, where in silico prediction is poor. I AM can also be applied to generate large data sets, that in turn can be applied to train and, therefore, improve in silico models by an extensive data input [41]. 

Two compounds are not considered in the analysis due to their name/ structure confusion. This is a parabolic correlation in terms of dog P with well-defined optimum dog P of 2.52 and suggests that log Poet is a suitable predictor for the human intestinal absorption in a parabolic fashion. It has been shown that compounds with log P values between zero and three are ideal for passive transcellular absorption across intestinal epithelia. ... 

Most Pi absorption by the small intestine occurs independently of the hormonal form of vitamin D. The reported role of 1,25-dihydroxyvitamin D in intestinal Pi transcellular absorption is somewhat unclear because of the normally rapid influx of Pi ions after a meal, but this hormone may enhance the late or slower uptake of Pi ions. Paracellular passive absorption of Pi ions may also occur, but the evidence for this is limited. 

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