Passive diffusion through membranes

Formation of Na+, K+-ATPase carrier molecules in the basolateral membrane of the tubular epithelial cells (promotes extrusion of Na+ ions from the cells and their movement into plasma by way of peritubular capillaries enhances the concentration gradient for passive diffusion through Na+ channels in the luminal membrane)... 

Potassium ion secretion. Potassium ions are secreted in the distal tubule and the collecting duct. These ions diffuse down their concentration gradient from the peritubular capillaries into the interstitial fluid. They are then actively transported up their concentration gradient into the tubular epithelial cells by way of the Na+, K+ pump in the basolateral membrane. Finally, potassium ions exit the epithelial cells by passive diffusion through K+ channels in the luminal membrane and enter tubular fluid to be excreted in the urine. 

Passive diffusion through the lipid bilayer of the epithelium can be described using the partition coefficient between octanol/water (log P) and A log P (the difference between the partition into octanol/water and heptane/ethylene glycol or heptane/ octanol) [157, 158], The lipophilicity of the drug (log P) (or rather log D at a certain pH) can easily be either measured or calculated, and is therefore generally used as a predictor of drug permeability. Recently, a method using artificial membrane permeation (PAMPA) has also been found to describe the passive diffusion in a similar manner to the Caco-2 cell monolayers [159]. 

Fig. 15.2. Physicochemical molecular descriptors affect the transport route utilised across the intestinal epithelium. To passively diffuse through the membrane (1), the compound (here illustrated with testosterone) should preferably be small, with a molecular weight <500 Da, as well as uncharged and fairly lipophilic. However, compounds that are too lipophilic can stick to the membrane and will not pass through the cells. The paracellular route (2), here exemplified with mannitol, is mainly utilised by smaller (Mw < 200 Da)...

Fig. 17. Confocal fluorescence imaging of [Zn(ATSM)] in IGROV cells (100 pM, where Q1 — Q2 = Me, M = Zn(II), R1 = R3 = H and R2 = R4 = Me, /ex = 488 nm, DMEM with 1% DMSO). Brightfield image shows formation of needle-like crystalline material on the cell plate (N.B. Small crystallites may be endocytosed by the cells rather than passively diffuse through the cell membrane).

A parameter (usually symbolized by P, and often containing a subscript to indicate the specific ion) that is a measure of the ease with which an ion can cross a unit area of membrane by simple (or passive) diffusion through a membrane experiencing a 1.0 M concentration gradient. For a particular biological membrane, the permeabilities are dependent on the concentration and activity of various channel or transporter proteins. In an electrically active cell (e.g., a neuron), increasing the permeability of K+ or CF will usually result in hyperpolarization of the membrane. Increasing will cause depolarization. 

Ammonification is another process that can result in N release. The simplest definition of the process is the release ofNH4 from organic matter (e.g., Herbert, 1999). It can occur by a number of different processes including remineralization by bacteria in the water column and sediments. Photochemical ammonification occurs abiotically when NH4+ is released from organic matter as a result of exposure to UV radiation (reviewed in Bronk, 2002 and Chapter 10 by Gryz-bowski and Tranvik, this volume). Ammonium efflux from cells has also been observed following urea uptake in a number of culture experiments (e.g., Price and Harrison, 1988 Rees and Bekheet, 1982 Uchida, 1976). The release may be due to passive diffusion through the cell membrane and is likely unavoidable because NH3 is lipid soluble. 

Thus, the nature of these membranes and the chemical and physical properties of the toxicant in question are important factors affecting uptake. The mechanisms by which chemical agents pass through the membranes include (1) filtration through spaces or pores in membranes (2) passive diffusion through the spaces or pores, or by dissolving in the lipid material of the membrane and (3) facilitated transport, whereby specialized transport systems carry water-soluble substances across the membrane by a lipid soluble "carrier" molecule, which complexes with the chemical. It can be seen then that, as far as the chemical properties are concerned, lipophilicity is the most important factor affecting absorption. 

The unbound drug in the systemic circulation is available to distribute extravascularly. The extent of distribution is mainly determined by lipid solubility and, for weak organic acids and bases, is influenced by the pK3/pH-dependent degree of ionization because only the more lipid-soluble non-ionized form can passively diffuse through cell membranes and penetrate cellular barriers such as those which separate blood from transcellular fluids (cerebrospinal and synovial fluids and aqueous humour). The milk-to-plasma equilibrium concentration ratio of an antimicrobial agent provides a reasonably... 

Another simple appHcation of the PSA is in assessing drug-like properties of molecules. Today, PSA is commonly used as an extension of the rule of 5. A high PSA indicates an increased risk of bioavailability problems for a compound. However, the predictivity of a PSA model must not be overstressed. The physico-chemical properties of a compound only influence its behavior in passive diffusion through a membrane. Other effects, such as active transport, are not considered at all. 

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