Active-transport pathways

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. 

In the absence of active transport pathways, the stereoselectivity in the tissue distribution of chiral drugs is affected by both binding to plasma and tissue proteins. Studies [104] in rats with disopyramide, flecainide, and verapamil have shown that the tissue binding of flecainide... 

The assessment of clearance is complicated by the numerous mechanisms by which compounds may be cleared from the body. These mechanisms include oxidative metabolism, most commonly by CYP enzymes, but also in some cases by other enzymes including but not limited to monoamine oxidases (MAO), flavin-containing monooxygenases (FMO), and aldehyde oxidase [45, 46], Non-oxidative metabolism such as conjugation or hydrolysis may be effected by enzymes such as glucuronyl transferases (UGT), glutathione transferases (GST), amidases, esterases, or ketone reductases, as well as other enzymes [47, 48], In addition to metabolic pathways, parent compound may be excreted directly via passive or active transport processes, most commonly into the urine or bile. 

Data analysis should focus on the development or refinement of the conceptual site model by analyzing data on source characteristics, the nature and extent of contamination, the contaminants transport pathways and fate, and the effects on human health and the environment. All field activities, sample management and tracking, and document control and inventory should be well managed and documented to ensure their quality, validity, and consistency. 

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. 

KW Gasser, J DiDomineco, UH Hopfer. (1988). Secretagogues activate chloride transport pathways in pancreatic zymogen granules. Am J Physiol 254 G93-G99. 

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. 

The use of Caco-2 cell monolayers has gained in popularity as an in vivo human absorption surrogate moreover, the monolayers are generally accepted as a primary absorption screening tool by several pharmaceutical companies [10]. However, Caco-2 cell permeability measurements exhibit certain limitations due to the mechanisms involved. Both passive and active pathways exist active transport tends to increase the absorption across the cells and, since Caco-2 cells overexpress the P-glycoprotein (P-gp) efflux pump, the absorption of some compounds across these cells may be underestimated. 

Secretory cells, including neurons, also possess a specialized regulated secretory pathway. Vesicles in this pathway have soluble proteins, peptides or neurotransmitters stored and concentrated within secretory vesicles. At that point, these vesicles are actively transported to a site for extracellular delivery in response to a specific extracellular signal. Exocytosis through regulated secretion accomplishes different functions, including the... 

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