Passive diffusion membrane transport

Absorption of some highly ionized compounds (e.g., sulfonic acids and quaternary ammonium compounds) from the gastrointestinal tract cannot be explained in terms of the transport mechanisms discussed earUer. These compounds are known to penetrate the Upid membrane despite their low Upid-water partition coefficients. It is postulated that these highly lipophobic drugs combine reversibly with such endogenous compounds as mucin in the gastrointestinal lumen, forming neutral ion pair complexes it is this neutral complex that penetrates the Upid membrane by passive diffusion. 

For ion pair transport to take place, organic anions combine with organic cations to form a neutral complex, which is then transported through the membrane by passive diffusion. 

The permeability of compounds through cell membranes is of great interest and importance for the elucidation of many biologic ceU functions. Most metabolically important substances are transported across membranes by active transport. Many other intrinsic compounds, as well as most drugs, are known to pass the membrane by passive diffusion. 

In contrast to active transport, passive transport as a whole does not involve energy consumption and, therefore, only can work down a concentration gradient (or other types of gradients, such as electrochemical potential, thermal, or pressure gradients). In other words, passive transport of molecules equalizes their chemical potential on both sides of the membrane. The process of passive transport can be subdivided into two different mechanisms passive diffusion and facilitated transport. Passive diffusion is a physico-chemical process, whereas in facilitated transport, molecules pass through the membrane via special channels or are translocated via carrier proteins. Both passive diffusion and facilitated transport, in contrast to active transport, follow a gradient, where facilitation merely lowers the activation energy for the transport process. 

Several types of absorptive mechanisms exist for nutrients including active transport, passive diffusion, facilitated diffusion, and endocytosis. End-ocytosis occurs when the outer plasma membrane surrounds soluble or particulate nutrients in the GI tract and engulfs the contents. This process is similar to phagocytosis. 

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. 

Evidence for a direct correlation between the turnover number for vinblastine-stimulated ATP hydrolysis and vinblastine transport rate was provided by Ambudkar and Stein [43]. Since compounds that interact with P-gp often exhibit a high lipid-water partition coefficient and can cross the lipid bilayer by passive diffusion, the stoichiometry between ATP hydrolysis and drug transport is difficult to assess. Using a permanently charged spin-labeled analogue of verapamil that cannot cross the membrane by passive diffusion [44], a direct correlation between ATP hydrolysis and drug transport was demonstrated [45]. 

In recent years, there has been increasing awareness regarding the importance of transporters in the absorption and disposition of NMEs. While the major portion of NMEs or marketed drugs traverse cell membranes by passive diffusion, there are numerous examples where the involvement of specialized transport mechanisms has been demonstrated. Examples include the role of oligopeptide transporters in the intestinal absorption of P-lactam antibiotics, angiotensinconverting enzyme (ACE) inhibitors, and novel NMEs as well as the role of P-glycoprotein (P-gp) in the secretion of molecules into the intestine [11,77—79]. Transfection of cells with the transporter protein of interest has permitted the evaluation of precise cellular mechanisms of uptake and transport of NMEs. Transfected cell lines by definition are tailor-made to overexpress the protein of... 

Estimates ability to cross lipid membranes through passive diffusion without active transport or efflux... 

Biological membranes have complex effects on passive transport by diffusion because they are structured as a mosaic of regions with distinct hydrophobic and hydrophilic properties. Consequently, polarity affects the ability of molecules to pass through biological membranes by passive diffusion. The ability of membrane proteins specifically to admit some polar molecules and exclude others dramatically affects the responses of biological membranes to concentration gradients. 

The PAMPA method is based on a 96-well plate platform that features a phospholipid membrane-soaked pad that separates an aqueous donor and receiver compartment. The membrane does not contain active transporters. The strategic use of PAMPA assays in drug discovery is based on the ability to screen large libraries and quickly determine trends based on the ability of compounds to permeate membranes by passive diffusion [83], In this way, quantitative structure activity relationships (QSAR) can be initiated based on this mechanism of absorption [84],... 

The basic mechanisms involved in solute transport across the plasma membrane include passive diffusion, facilitated diffusion, and active transport. Active transport can be further subdivided into primary and secondary active transport. These mechanisms are depicted in Figure 2-4. 

With respect to transcellular permeability, the relationship of solute structure with permeability depends on the mechanism. Historically, a passive diffusion pathway is assumed for most solutes. Nevertheless, a great number of solutes are identified as being associated with active absorption and secretary processes in intestinal epithelial cells. Additionally, although active transport involves specific interactions between a solute and transporter, passive diffusion is dependent on solute partitioning into the cellular plasma membrane and the diffusion coefficient within the membrane. 

An important first step in the hepatic metabolism of proteins and peptides is the uptake into hepatocytes. Small peptides may cross the hepatocyte membrane via passive diffusion if they have sufficient hydrophobicity. Uptake of larger peptides and proteins is facilitated via various carrier-mediated, energy-dependent transport processes. Receptor-mediated endocytosis is an additional mechanism for uptake into hepatocytes (see Sect. 8.3.4.5) [28]. In addition, peptides such as metkephamid can already be metabolized on the surface of hepatocytes or endothelial cells [41]. 

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