Passive transport pathway

Schematic representation of the major pathways for the transport of Ca across cellular membranes. PM, plasma membrane ER(SR), endoplasmic reticulum (sarcoplasmic reticulum) M, mitochondria A P, difference in membrane potential. The transport proteins shown are 1 and 2, PM and ER(SR) Ca -ATPases 3 and 4, PM and ER(SR) receptor-mediated Ca " channels 5 and 6, PM and M (inner-membrane) Na /Ca exchangers 7 and 8, PM and M voltage-sensitive Ca channels. In addition, some not-well-defined passive transport pathways are indicated by dashed arrows.

The passive transport pathway is nonsaturable and paracellular. It occurs throughout the small intestine and is unaffected by calcium status or parathyroid hormone (PTH). It is relatively independent of 1,25(0H)2D3, although this metabolite has been foimd by some investigators to increase the permeability of the paracellular pathway. A substantial amoimt of calcium is absorbed by passive transport in the ileum due to the relatively slow passage of food through this section of the intestine. The amoimt of calcium absorbed by passive transport will be proportional to the intake and bioavailability of calcium consumed. 

While both paracellular and passive transcellular pathways are available to a solute, the relative contribution of each to the observed transport will depend on the properties of the solute and the membrane in question. Generally, polar membrane-impermeant molecules diffuse through the paracellular route, which is dominated by tight junctions (Section III.A). Exceptions include molecules that are actively transported across one or both membrane domains of a polarized cell (Fig. 2). The tight junction provides a rate-limiting barrier for many ions, small molecules, and macromolecules depending on the shape, size, and charge of the solute and the selectivity and dimensions of the pathway. 

Let us systematically delineate the transport pathways of the nondissociated and protonated species of the P-blockers by applying Eq. (82). The insignificance of the mass transfer resistance of the ABL on the overall transport process, as evidenced by the lack of influence of stirring on Pe, indicates that the passive diffusional kinetics are essentially controlled by the cell monolayer and filter. Therefore, Eq. (82) simplifies to... 

There are two pathways by which a drug molecule can cross the epithelial cell the transcellular pathway, which requires the drug to permeate the cell membranes, and the paracellular pathway, in which diffusion occurs through water-filled pores of the tight junctions between the cells. Both the passive and the active transport processes may contribute to the permeability of drugs via the transcellular pathway. These transport pathways are distinctly different, and the molecular properties that influence drug transport by these routes are also different (Fig. 

Figure 2.2 Schematic diagram of the physical model for passive transport of solutes across the intestinal membrane. The bulk aqueous solution with an aqueous boundary layer (ABL) on the mucosal side is followed by a heterogeneous membrane consisting of lipoidal and aqueous channel pathways and thereafter by a sink on the serosal side. (Adapted from Ho et al. [5]).

Keywords Colon Controlled release Sustained release Rat Single-pass perfusion Recirculation Closed loop Carrier-mediated transport Passive transport Membrane permeability P-glycoprotein Paracellular pathway Transcellular pathway... 

Figure 8.2 Possible drug transport pathways across the intestinal mucosa, illustrating transcellular (1) and paracellular (2) modes of passive transport, transcytosis (3), carrier-mediated transport (4), and efflux transport (5). A combination of these routes often defines the overall transepithelial transport rate of nutrients and drugs.

Transport across the cell membrane may occur via different routes. Some of these transport processes are energy dependent and therefore termed active others are independent from energy, thus passive. Passive transport phenomena, for example, transcellular transport, are triggered by external driving forces, such as concentration differences, and do not require metabolic activity. However, generally, they are restricted to small lipophilic compounds. In contrast, active transport phenomena, such as active carrier-mediated transport or vesicular pathways, take course independent from external driving... 

Major transport pathways in Caco-2 monolayers. A Passive transcellular B Passive paracellular C Transporter-mediated apical uptake D Transporter-mediated apical efflux E Transporter-mediated basolateral efflux F Transporter-mediated basolateral uptake. 

HDL may be taken up in the liver by receptor-mediated endocytosis, but at least some of the cholesterol in HDL is delivered to other tissues by a novel mechanism. HDL can bind to plasma membrane receptor proteins called SR-BI in hepatic and steroidogenic tissues such as the adrenal gland. These receptors mediate not endocytosis but a partial and selective transfer of cholesterol and other lipids in HDL into the cell. Depleted HDL then dissociates to recirculate in the bloodstream and extract more lipids from chylomicron and VLDL remnants. Depleted HDL can also pick up cholesterol stored in extrahepatic tissues and carry it to the liver, in reverse cholesterol transport pathways (Fig. 21-40). In one reverse transport path, interaction of nascent HDL with SR-BI receptors in cholesterol-rich cells triggers passive movement of cholesterol from the cell surface into HDL, which then carries it back to the liver. In a second pathway, apoA-I in depleted HDL in-... 

One fascinating aspect of hydrocarbon evolution as semiochemicals lies in the documented chemical mimicry systems between parasite and host (Chapter 14, this book). Some systems operate by camouflage and passive transport, others by loss of parasite specific compounds, some use de novo synthesis of the same host mixture or part of the mixture, and others are as yet unrevealed. To date we are mostly limited to the description of the host-parasite chemical coevolution (or arms race), but we hope in the near future to be able to associate biosynthetic pathways as well as gene expression with such evolutionary processes. 

When a saturable transporter is involved in the permeation process, the permeability is no longer a constant value but is dependent on the concentration of the substrate. In that case it is necessary to characterize the parameters of the carrier-mediated process, Km, the Michaelis-Menten constant related with the affinity by the substrate and Vmax, the maximal velocity of transport. If a passive diffusion process occurs simultaneously to the active transport pathway then it is necessary to evaluate the contribution of each transport mechanism. An example of how to characterize the parameters in two experimental systems and how to correlate them are described in the next section. 

Fig. 12.1 Schematic representation of the three transepithelial intestinal pathways (a) trans-cellular active transport, (b) transcellular passive transport, (c) paracellular transport (Fasano...

The most difficult and interesting question about H+-ATPase is how chemical reaction (ATP synthesis/ hydrolysis) is coupled with vectorial H+ conduction. The mechanism for the stoichiometric coupling between chemical reaction and vectorial transport of ions is a universal question for ion-motive ATPases. The Fo portion is a passive proton pathway but becomes a regulated pathway after the binding of Fi. Mutant analyses suggest that the y subunit has regulatory role(s) for proton conduction. 

The paracellular route is a passive, diffusional transport pathway, taken by small, hydrophilic molecules, for example mannitol, which can pass through the various types of junctions between adjacent epithelial cells. The rate of passive diffusion follows Fick s Law, which is described in detail below. Passive diffusion is driven by a concentration gradient and is inversely related to molecular weight. This route is therefore not suitable for large molecular weight drags, which are too large to cross between cell junctions. 

Prognosis of a compounds permeability should be made stressing limitations of the model. There is no bioavailability prognosis from in vitro data - a cellular assay can provide only permeability potential through a biological membrane. The membrane, in most cases CACO-2 cells, is very similar to what we observe in vivo in the small intestine and resembles many characteristics to in vivo enterocytes. CACO-2 cells can be used for prediction of different pathways across intestinal cells. Best correlation occurs for passive transcellular route of diffusion. Passive paracellular pathway is less permeable in CACO-2 and correlations are rather qualitative than quantitative for that pathway. CACO-2 cells are an accepted model for identification of compounds with permeability problems, for ranking of compounds and selection of best compounds within a series. Carrier-mediated transport can be studied as well using careful characterization of transporters in the cell batch or clone as a prerequisite for transporter studies. 

The system depends on an electron transport pathway that transfers electrons from NADPH through a flavoprotein (NADPH cytochrome P-450 reductase) to cytochrome P-450 that is the terminal oxidase of the chain (10). The xenobiotic first forms a complex with the oxidized form o cytochrome P-450 which is reduced by an electron passing down the chain from NADPH. The reduced cytochrome P-450/substrate complex then reacts with and activates molecular oxygen to an electrophilic oxene species (an electron deficient species similar to singlet oxygen) that is transferred to the substrate with the concommitant formation of water. Cytochrome P-450 thus acts primarily as an oxene transferase (2). Substrate binding is a relatively nonspecific, passive process that serves to bring the xenobiotic into close association with the active center and provide the opportunity for the oxene transfer to occur. 

Figure 1 Copper transport pathway. Copper is absorbed in the intestine and becomes bound to amino acids, mainly histidine and albumin. Prior to uptake, Cu(II) is reduced to Cu(I) by a membrane-bound reductase and enters the cell via a passive transporter. Once in the cell, copper becomes bound to copper chaperones responsible for delivering copper to specific proteins. The Wilson/Menkes ATPase accepts copper from these chaperones and pumps it into the Golgi for incorporation into various proteins such as ceruloplasmin (Cp). Ceruloplasmin may also play a role in delivering copper to peripheral tissues via cell-surface receptors that internalize the protein. The Wilson disease ATPase may also play a role in the elimination of copper into the bile...

The compounds can cross the membranes by passive processes, which depend only on the concentration gradient on both sides of the barrier, or by active ones, which are mediated by the interaction of the compound with a protein. The passive processes of the epithelial cells in the gastrointestinal tract include passive transport through the cell (trans-cellular pathway) or in the space between the cells (para-cellular pathway) [18]. 

Only a few laser scanning confocal microscopy (LSCM) studies have examined the passive permeation pathways of molecules across the skin. Cullander and Guy [36] showed that calcein, a multiply charged fluorophore, penetrates minimally into the SC of hairless mouse skin (HMS). Similar studies by Turner et al. [37a] have confirmed this observation. Indeed, it is the hydrophilic, charged nature of calcein that prevents its facile partitioning into the lipophilic intercellular spaces of the SC. Although some penetration of calcein into the SC intercellular domains, and into the pilary canal of the hair follicles, is observed, the total passive epidermal transport of calcein was negligible. 

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