Membrane transport, neutral forms

MacrotetroHdes of the valinomycin group of electrically neutral antibiotics form stable 1 1 complexes with alkaH metal ions that increase the cation permeabiHty of some biological and artificial lipophilic membranes. This solubiHzation process appears to have implications in membrane transport research (30) (see Antibiotics, peptides). 

In the transport across a phospholipid bilayer by passive diffusion, the permeability of the neutral form of a molecule is 10X times greater than that of the charged form. For the epithelium, the discrimination factor is 105. The basement membrane (Fig. 2.5) allows passage of uncharged molecules more readily than charged species by a factor of 10 [76]. 

Fig. 6 Another mechanism of amino acid transport rests on the idea of the reversible formation of the neutral form, which passes through the membrane much faster...

Although uronium behaves very similarly to guanidinium in the com-plexation discussed, the binding and extraction of urea are a challenging point. Actually, the conversion of urea to uronium requires acidification with, e.g., perchloric acid, which is inconvenient for practical applications. The problem with urea itself is that this neutral molecule forms only weak complexes with various hosts [132,133]. Some initial attempts to overcome the difficulty involved crowns with intra-anular acidic groups and (proton-ated) pyridino crowns [126,134,135], designed to protonate urea upon complexation. However, it was found that these hosts are not efficient in extraction and membrane transport the pyridine compounds failed to protonate urea and have an unfavorable tendency toward self-complexation [136]. Acidic functionalities help to bind urea strongly, but their nature simultaneously manifested itself in unfavorably low host lipophilicity. 

Many alkaloids have strong biological activities in man. In part this can be explained by structural relationship with important signal compounds (neurotransmitters) such as dopamine, acetylcholine, noradrenaline, and serotonin. The fact that alkaloids are water soluble under acidic conditions and lipid soluble under neutral and basic conditions give them unique properties for medicinal use, as they can be transported in the protonated form, and can pass membranes in the neutral form. In fact most synthetic medicines do contain one or more tertiary nitrogens. 

Extensive studies including both inner-sphere and outer-sphere complexation of cations were performed with lasa-locid A, which is a small natural ionophore containing a salicylic acid fragment (Figure 1). The ability of lasalocid to form neutral outer-sphere complexes with species like Co(NH3)(5 +, Cr(bpy)3 ", Pt(bpy)(NH3)2 " " allows one to use it as an ionophore for the membrane transport (including chiroselective transport) of such species. The lasalocid ionophore also was shown to be an efficient carrier for toxic water-soluble metal cations such as Pb + and Cd + across artificial flat-sheet-supported liquid membranes, which represent a potential system for separation of these cations. 

Most of the conductivity measurements were performed on the SPI acidic form since it is the relevant value for the fuel cell application. Nevertheless, a few data were obtained on neutralized forms [141,146,159]. Rollet et al. used sodium and tetramethylammonium ions to study the transport processes within the membranes and a transport anisotropy was clearly observed from longitudinal and transversal measurements [146]. 

Cholanic acid also possesses the ability of transporting cations across a lipophilic membrane but the selectivity is not observed because it contains no recognition sites for specific cations. In the basic region, monensin forms a lipophilic complex with Na+, which is the counter ion of the carboxylate, by taking a pseudo-cyclic structure based on the effective coordination of the polyether moiety. The lipophilic complex taken up in the liquid membrane is transferred to the active region by diffusion. In the acidic region, the sodium cation is released by the neutralization reaction. The cycle is completed by the reverse transport of the free carboxylic ionophore. 

The evaluation of the apparent ionization constants (i) can indicate in partition experiments the extent to which a charged form of the drug partitions into the octanol or liposome bilayer domains, (ii) can indicate in solubility measurements, the presence of aggregates in saturated solutions and whether the aggregates are ionized or neutral and the extent to which salts of dmgs form, and (iii) can indicate in permeability measurements, whether the aqueous boundary layer adjacent to the membrane barrier, Umits the transport of drugs across artificial phospholipid membranes [parallel artificial membrane permeation assay (PAMPA)] or across monolayers of cultured cells [Caco-2, Madin-Darby canine kidney (MDCK), etc.]. 

Burgmayer and Murray [40] reported electrically controlled resistance to the transport of ions across polypyrrole membrane. The membrane was formed around a folded minigrid sheet by the anodic polymerization of pyrrole. The ionic resistance, measured by impedance, in 1.0 M aqueous KC1 solution was much higher under the neutral (reduced) state of the polymers than under the positively charged (oxidized) state. The redox state of polypyrrole was electrochemically controlled this phenomenon was termed an ion gate, since the resistance was varied from low to high and vice versa by stepwise voltage application. 

The dogma based on the pH-partition theory that only neutral species cross a membrane has been challenged [11]. Using cyclic voltammetry, it was shown that compounds in their ionized form pass into organic phases and might well cross membranes in this ionized form [32]. Various ways that an ion may cross a membrane have been described [33], including transport as an ion (trans- and/or para-... 

P-gp substrates are in general either neutral or cationic at physiological pH (weak bases). Weak bases can cross the lipid membrane in the uncharged form and reprotonate in the negatively charged cytosolic leaflet of the membrane. With a few exceptions (e.g., the tetraphenyl phosphonium ion, which can reach the cytosolic membrane leaflet due to charge delocalization [70]), permanently charged cations do not cross the cell membrane and therefore cannot interact with P-gp in intact cells. They can, however, insert into the cytosolic leaflet in inside-out cellular vesicles and are then transported by P-gp [42, 71]. 

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