Polar molecule membrane permeability

The chemical space is a multidimensional area with each dimension defined by a descriptor which can be molecular weight, polarity, solubility, membrane permeability, binding constant. H-bond-ing properties etc. and encompasses all small carbon-based molecules that could in principle be created [5]. 

With the exception of rather small polar molecules, the majority of compounds, including drugs, appear to penetrate biological membranes via a lipid route. As a result, the membrane permeability of most compounds is dependent on K0/w. The physicochemical interpretation of this general relationship is based on the atomic and molecular forces to which the solute molecules are exposed in the aqueous and lipid phases. Thus, the ability of a compound to partition from an aqueous to a lipid phase of a membrane involves the balance between solute-water and solute-membrane intermolecular forces. If the attractive forces of the solute-water interaction are greater than those of the solute-membrane interaction, membrane permeability will be relatively poor and vice versa. In examining the permeability of a homologous series of compounds... 

Using liposomes made from phospholipids as models of membrane barriers, Chakrabarti and Deamer [417] characterized the permeabilities of several amino acids and simple ions. Phosphate, sodium and potassium ions displayed effective permeabilities 0.1-1.0 x 10 12 cm/s. Hydrophilic amino acids permeated membranes with coefficients 5.1-5.7 x 10 12 cm/s. More lipophilic amino acids indicated values of 250 -10 x 10-12 cm/s. The investigators proposed that the extremely low permeability rates observed for the polar molecules must be controlled by bilayer fluctuations and transient defects, rather than normal partitioning behavior and Born energy barriers. More recently, similar magnitude values of permeabilities were measured for a series of enkephalin peptides [418]. 

The lipid bilayer arrangement of the plasma membrane renders it selectively permeable. Uncharged or nonpolar molecules, such as oxygen, carbon dioxide, and fatty acids, are lipid soluble and may permeate through the membrane quite readily. Charged or polar molecules, such as glucose, proteins, and ions, are water soluble and impermeable, unable to cross the membrane unassisted. These substances require protein channels or carrier molecules to enter or leave the cell. 

To reach such a site, a molecule must permeate through many road blocks formed by cell membranes. These are composed of phospholipid bilayers - oily barriers that greatly attenuate the passage of charged or highly polar molecules. Often, cultured cells, such as Caco-2 or Madin-Darby canine kidney (MDCK) cells [1-4], are used for this purpose, but the tests are costly. Other types of permeability measurements based on artificial membranes have been considered, the aim being to improve efficiency and lowering costs. One such approach, PAMPA, has been described by Kansy et al. [5],... 

Figure 6.11. Intracellular Ca2+ levels during neutrophil activation with fMet-Leu-Phe. Neutrophil suspensions were loaded with Fluo-3 AM for 15 min. This molecule is membrane permeable but cleaved by intracellular esterase activity to yield the polar molecule Fluo-3, which is thus trapped within the cell. The neutrophils were then suspended in buffer that was devoid of Ca2+, and treated as shown. In (a), 1 mM Ca2+ and 1 /tM fMet-Leu-Phe were added to the suspension, as indicated by the arrows. In (b), 1 mM EGTA and 1 pM fMet-Leu-Phe were added as shown. Thus, in (a), the change in intracellular Ca2+ is due to mobilisation of intracellular Ca2+ stores and the influx of extracellular Ca2+, whereas in (b), the Ca2+ rise is due solely to release of Ca2+ from intracellular stores.

In eukaryotic cells, electron transport and oxidative phosphorylation occur in mitochondria. Mitochondria have both an outer membrane and an inner membrane with extensive infoldings called cristae (fig. 14.2). The inner membrane separates the internal matrix space from the intermembrane space between the inner and outer membranes. The outer membrane has only a few known enzymatic activities and is permeable to molecules with molecular weights up to about 5,000. By contrast, the inner membrane is impermeable to most ions and polar molecules, and its proteins include the enzymes that catalyze oxygen consumption and formation of ATP. The role of mitochondria in 02 uptake, or respiration, was demonstrated in 1913 by Otto Warburg but was not fully confirmed until 1948, when Eugene Kennedy and Albert Lehninger showed that mitochondria carry out the reactions of the TCA cycle, the transport of electrons to 02, and the formation of ATP. 

Cholesterol ((3(3)-cholest-5-en-3-ol) is a major non-phospholipid component of animal membranes and is the principal sterol of animals. Cholesterol is also amphipathic, the 3-hydroxy being polar and the rest of the molecule hydrophobic. Cholesterol can insert into phospholipid bilayers, lowering membrane permeability and lowering the melting point of membranes (i.e. making the membranes less ordered and more fluid). 

The results of permeability studies of lipid vesicles and electrical-conductance measurements of planar bilayers have shovm that lipid bilayer membranes have a very low permeability for ions and most polar molecules. Water is a conspicuous exception to this generalization it readily traverses such membranes because of its small size, high concentration, and lack of a complete charge. The range of measured permeability coefficients is very wide (Figure 12.15). For example, Na+ and K+ traverse these membranes 10 times as slowly as does H2O. Tryptophan, a zwitterion... 

The lipid bilayer of biological membranes, as discussed in Chapter 12. is intrinsically impermeable to ions and polar molecules. Permeability is conferred by two classes of membrane xoXems, pumps and channels. Pumps use a source of free energy such as ATP or light to drive the thermodynamically uphill transport of ions or molecules. Pump action is an example of active transport. Channels, in contrast, enable ions to flow rapidly through membranes in a downhill direction. Channel action illustrates passive transport, or facilitated diffusion. 

Many substances, particularly polar molecules, cross membranes at rates greater than those predicted from solubility and permeability data. Some can cross membranes against a concentration gradient. Unexpectedly high membrane permeability is related to transport proteins. Many transport proteins have been identified, cloned, and sequenced. Current knowledge has permitted an operational definition of carrier proteins as channels, carriers, and pumps. The current state of the art in identification and characterization of these systems has been described by Wright. ... 

Initial speculation on the existence of small aqueous pores in membranes was based on high membrane permeability of small polar molecules. For example, the permeability of water is 1000-fold more, and that of urea 10- to 100-fold more, than predicted. These types of observations led to the prediction of aqueous channels with radii of approximately 4 A. 

It is in the form of bilayers that phosphoglycerides are believed to exist in cell membranes. They constitute walls that not only enclose the cell but also very selectively control the passage, in and out, of the various substances—nutrients, waste products, hormones, etc.—even from a solution of low concentration to a solution of high concentration. Now, many of these substances that enter and leave the cells are highly polar molecules like carbohydrates and amino acids, or ions like sodium and potassium. How can these molecules pass through cell membranes when they cannot pass through simple bilayers And how can permeability be so highly selective ... 

Because BLM made of pure lipid or oxidized cholesterol In common salt solutions are nonconducting, the physical properties of BLM are with one exception similar to those of a liquid hydrocarbon layer of equivalent th ckness. The Interfaclal tension of BLM Is less than 5 dynes cm, which Is approximately one order of magnitude lower than that of the hydrocarbon/water Interface. This low Interfaclal tension Is due to the presence of polar groups at the Interface. BLM have negligible permeability for Ions and most polar molecules. Permeability to water Is comparable to that of biological membranes. The permeability to water of Chlorophyll BLM, as determined by an osmotic flew method. Is 50 pm s, which Is in-the range of phospholipid BLM but six times larger than that of oxidized cholesterol BLM. 

Similar to studies on the porosity of capsule membranes using series of tracer molecules of different size, one may use molecules of similar size which differ in a single other parameter like polarity, shape, flexibility, etc., to yield additional information about the membrane structure. As all these observations are performed in the state of equilibrium distribution, there are no restrictions in terms of the overall duration of the measurement. Overall, systematic studies on the membrane permeability could elucidate a variety of details on the capsule structure and the possible release properties. 

A simple method to measure the membrane permeability to specific molecules has been presented by G. Battaglia and coworkers [141], The authors encapsulated highly hydrophilic 3,3, 3//-phosphinidynetris-benzenesulfonic acid (PH) into polyethylene oxidc)-co-poly(butylene oxide) (EB) vesicles and monitored its reaction with 5,5/-dithiobis-2-nitrobenzoic acid (DTNB) penetrating the membrane from the exterior. The reaction rate (amount of the formed product as a function of time after DTNB addition) measured with IJV/Vis was directly correlated to the permeability of the permeating molecule. A comparison of these results with the permeability of egg yolk phosphatidylcholine (PC) vesicles showed that EB membranes have a more selective permeability toward polar molecules than the phospholipids membranes. Also in this case the permeability appeared to depend on the membrane thickness as predicted by Fick s first law. 

Large differences in permeabilities of membranes can be attributed to differences in interchain displacement and flexibility related to polar and steric effects. The polar molecules such as polytetrafluoroethylene have a stronger tendency to form rigid associations leading to crystal formation than nonpolar molecules. Polytetrafluoroethylene polymers are highly... 

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