Absorption passage across membranes

Mammalian intestinal absorption requires the presence of two receptors and two transporters, which is itself a unique feature. Specific transporters such as intrinsic factor, transcobalamin, and haptocorrin have been characterized,1113 as well as a number of receptors for passage across cell membranes. A number of biochemical studies on cell uptake1114 and receptors1115,1116 of cobala-mins have been reported. Genetic disorders that impair the synthesis, transport, or transmembrane passage of cobalamins and their consequences have been reviewed.1117,1118... 

An alternative method which could be used to establish the fraction of protein that actually reaches the alveoli is the so-called co-aerosohzation. If a protein is aerosolized from a solution that also contains another low molecular weight substance (deposition marker), it can be assumed that the fractions of protein and deposition marker reaching the alveoli will be the same. The deposition marker should be a substance with a known alveolar epithelial membrane passage (e.g. tobramycin or a decapeptide) which does not undergo absorption after oral administration. The fraction of the deposition marker that is deposited in the alveoli can be established from plasma (and urine) measurements of the deposition marker. The maximum fraction of protein that can pass the alveolar membrane whl then be known. The ratio between the deposited fraction and the fraction that has been absorbed into the systemic circulation (as can be estabhshed form plasma or urine analysis) will provide an estimation of the protein passage across the alveolar membrane. 

An ability to penetrate lipid bilayers is a prerequisite for the absorption of drugs, their entry into cells or cellular organelles, and passage across the blood-brain barrier. Due to their amphiphilic nature, phospholipids form bilayers possessing a hydrophilic surface and a hydrophobic interior (p. 20). Substances may traverse this membrane in three different ways. 

Mechanisms involved in the passage of drugs across membranes. (Adapted with permission from Smyth DH. Absorption and Distribution of Drugs. Baltimore Williams Wilkins, 1964 and Forth W and Rummel W (eds.). Pharmacology of Intestinal Absorption Gastrointestinal Absorption of Drugs. Vols. 1 and 2. Oxford, UK Pergammon, 1975). 

Although there are several sites of first contact between a foreign compound and a biological system, the absorption phase (and also distribution and excretion) necessarily involves the passage across cell membranes whichever site is involved. Therefore, it is important first to consider membrane structure and transport in order to understand the absorption of toxic compounds. 

Regardless of the route of exposure, absorption of a chemical substance from any site of exposure involves its passage across cellular membranes. Absorption of a substance includes the following processes in succession ... 

Physicochemical properties are critical determinants of a substance s ability to be absorbed (Dethloff, 1993 DeVito, 1996 Klaassen and Rozman, 1991). Table 11.1 lists the physicochemical properties that most significantly govern passage across cellular membranes and absorption. 

Facilitated diffusion is very similar to passive diffusion with the difference that transfer across membranes is assisted by the participation of carrier proteins embedded in the membrane bilayer. Again, the direction of passage will be from the side of the membrane with high concentration of a chemical to the side with low concentration this also occurs without energy expenditure by the cell. Such a process is somewhat specific in the sense that it applies to molecules that are able to bind to a carrier protein. Absorption of nutrients such as glucose and amino acids across the epithelial membrane of the gastrointestinal tract occurs by facilitated diffusion. Since a finite number of carriers are available for transport, the process is saturable at high concentrations of the transported molecules and competition for transport may occur between molecules of similar structure. 

Absorption Distribution Metabolism Excretion GI tract, lungs, skin Storage in tissues (plasma proteins, liver and kidney, fat, bone), blood-brain barrier, passage across the placenta, membrane permeability Liver, lungs, kidney, brain, phase I, phase II metabolism Urinary, fecal, exhalation, milk, sweat, sahva... 

Drug distribution in such sites or compartments is a complex process that depends on the systemic circulation concentration and subsequent passage across single cell endothelial or epithelial membranes with specialized physical and molecular barrier functionality. For certain orally administered AIDS medications (e.g., zidovudine and didanosine), oral absorption is limited because of poor absorption from the G1 tract, enzymatic biotransformation in the intestinal epithelium, or first-pass effects (Sinko et al., 1995, 1997). For other AIDS drugs (e.g., protease inhibitors), oral absorption may be complete however, drug distribution into the brain is limited by drug efflux proteins, which promiscuously interact and translocate lipophilic substrates back into blood as they diffuse into the BBB endothelium (Edwards et al., 2005 Kim et al., 1998). 

The absorption, distribution, metabolism, and excretion of a drug all involve its passage across cell membranes (Figure 1-1). 

In Section III, emphasis was placed on flux kinetics across the cultured monolayer-filter support system where the passage of hydrophilic molecular species differing in molecular size and charge by the paracellular route was transmonolayer-controlled. In this situation, the mass transport barriers of the ABLs on the donor and receiver sides of the Transwell inserts were inconsequential, as evidenced by the lack of stirring effects on the flux kinetics. In this present section, the objective is to give quantitative insights into the permeability of the ABL as a function of hydrodynamic conditions imposed by stirring. The objective is accomplished with selected corticosteroid permeants which have been useful in rat intestinal absorption studies to demonstrate the interplay of membrane and ABL diffusional kinetics (Ho et al., 1977 Komiya et al., 1980). 

In an effort to address the poor membrane permeation of L-767,679, the benzyl ester pro-drug, L-775,318 was synthesized (Fig. 13.2) The latter compound exhibited significant lipophilicity (log P = 0.7) that was consistent with improved potential to cross the enterocyte membrane. However, this did not lead to a marked improvement in absorption potential (in the rat), as intestinal hydrolysis and counter-transport combined to prevent significant passage of the compound across Caco-2 cells and the rat gut. 

Compounds can cross biological membranes by two passive processes, transcellu-lar and paracellular mechanisms. For transcellular diffusion two potential mechanisms exist. The compound can distribute into the lipid core of the membrane and diffuse within the membrane to the basolateral side. Alternatively, the solute may diffuse across the apical cell membrane and enter the cytoplasm before exiting across the basolateral membrane. Because both processes involve diffusion through the lipid core of the membrane the physicochemistry of the compound is important. Paracellular absorption involves the passage of the compound through the aqueous-filled pores. Clearly in principle many compounds can be absorbed by this route but the process is invariably slower than the transcellular route (surface area of pores versus surface area of the membrane) and is very dependent on molecular size due to the finite dimensions of the aqueous pores. 

The nasal epithelium possesses selective absorption characteristics similar to those of a semipermeable membrane, i.e., it allows a rapid passage of some compounds while preventing the passage of others. The process of transportation across the nasal mucosa involves either passive diffusion, via paracellular or transcellular mechanisms, or occurs via active processes mediated by membrane-bound carriers or membrane-derived vesicles involving endo- or transcytosis. 

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