Transport across epithelial membranes (original) (raw)
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All cells are generally separated from their surrounding environment by plasma membrane. In addition, the eukaryotic cells are compartmentalized by intracellular membranes that form the boundaries and internal structures of various organelles.Thesebiological membranes are semi-permeable in nature that is their permeability properties ensure that the specific molecules and ions readily enter the cell and the waste products leave the cell. These movements of solutes into the cell are mediated through the action of specific transport proteinsthat arepresent on the cell membrane. Such proteins are therefore required for movements of ions, such as Na + , K + , Ca2 + , and Cl -, as well as metabolites such as pyruvate, amino acids, sugars, and nucleotides, and even water. Transport proteins are also responsible for biological electrochemical phenomena such as neurotransmission.
Drug Discovery Today, 2011
All cells necessarily contain tens, if not hundreds, of carriers for nutrients and intermediary metabolites, and the human genome codes for more than 1000 carriers of various kinds. Here, we illustrate using a typical literature example the widespread but erroneous nature of the assumption that the 'background' or 'passive' permeability to drugs occurs in the absence of carriers. Comparison of the rate of drug transport in natural versus artificial membranes shows discrepancies in absolute magnitudes of 100-fold or more, with the carrier-containing cells showing the greater permeability. Expression profiling data show exactly which carriers are expressed in which tissues. The recognition that drugs necessarily require carriers for uptake into cells provides many opportunities for improving the effectiveness of the drug discovery process.
Computational Model for Membrane Transporters. Potential Implications for Cancer
Frontiers in Cell and Developmental Biology, 2021
To explain the increased transport of nutrients and metabolites and to control the movement of drug molecules through the transporters to the cancer cells, it is important to understand the exact mechanism of their structure and activity, as well as their biological and physical characteristics. We propose a computational model that reproduces the functionality of membrane transporters by quantifying the flow of substrates through the cell membrane. The model identifies the force induced by conformational changes of the transporter due to hydrolysis of ATP, in ABC transporters, or by an electrochemical gradient of ions, in secondary transporters. The transport rate is computed by averaging the velocity generated by the force along the paths followed by the substrates. The results obtained are in accordance with the experiments. The model provides an overall framework for analyzing the membrane transport proteins that regulate the flows of ions, nutrients and other molecules across t...
Water transport across biological membranes
FEBS Letters, 1994
The rate of the lateral diffusion of straight-chain phospholipids predicts the rate of water diffusion through bilayers. A new model of lipid dynamics integrates these processes. Substances such as cholesterol that reduce water diffision proportionally reduce lateral diffusion. The model yields a number of predictions about the dynamics of the lipids at the T,,, and suggests different mechanisms for how water diffuses across bilayers of other-thanstraight-chain lipids, and how proteins bind to membranes. A second recent development in water transport across biological membranes is the discovery of a ubiquitous family of water transport proteins that facilitate large-volume water translocation. Like water diffusion through lipid bilayers, water transport by these proteins is directed by osmosis and is therefore under the control of ATP and ion pumps. The presence of water transport proteins in membranes is often regulated by hormones.
COMPLEX SYSTEMS FOR DRUG TRANSPORT ACROSS CELL MEMBRANES
Chemistry: Bulgarian Journal of Science Education, 2015
Targeted drug delivery to specific tissues or cell compartments in the human organism is an advantageous route to overcoming multidrug resistance or reducing undesired side effects of pharmaceutics. Efficient specific targeting requires associating the drug with a carrier molecule. A multitude of compounds and assemblies have been tested as transporting moieties. This review summarizes the various classes of nanocarrier constructs, which have been proposed for transferring a class of potent chemotherapeutic agents, namely, anthracycline antibiotics through cell membranes. The building principles of the delivery systems are outlined and their pros and cons are discussed. Wherever available, the results from molecular simulations are presented. Special attention is paid to peptide-based systems in general and to a special type of peptides in particular-the cell-penetrating peptides, which may be used as building blocks of new systems for targeted drug delivery.
Does transbilayer diffusion have a role in membrane transport of drugs?
Drug Discovery Today, 2012
The existing consensus on coexistence of transbilayer diffusion and carrier-mediated transport as two main mechanisms for drugs crossing biological membranes was recently challenged by a systems biology group. Their transporters-only hypothesis is examined in this article using published experimental evidence. The main focus is on the key claim of their hypothesis, stating that 'the drug molecules cross pure phospholipid bilayers through transient pores that cannot form in the bilayers of cell membranes, and thus transbilayer drug transport does not exist in cells'. The analysis shows that the prior consensus remains a valid scientific view of the membrane transport of drugs.
Membrane transporters in drug development
Nature Reviews Drug Discovery, 2010
Membrane transporters can be major determinants of the pharmacokinetic, safety and efficacy profiles of drugs. This presents several key questions for drug development, including which transporters are clinically important in drug absorption and disposition, and which in vitro methods are suitable for studying drug interactions with these transporters. In addition, what criteria should trigger follow-up clinical studies, and which clinical studies should be conducted if needed. In this article, we provide the recommendations of the International Transporter Consortium on these issues, and present decision trees that are intended to help guide clinical studies on the currently recognized most important drug transporter interactions. The recommendations are generally intended to support clinical development and filing of a new drug application. Overall, it is advised that the timing of transporter investigations should be driven by efficacy, safety and clinical trial enrolment questions (for example, exclusion and inclusion criteria), as well as a need for further understanding of the absorption, distribution, metabolism and excretion properties of the drug molecule, and information required for drug labeling.
Biophysical Journal, 1986
There exist many examples of membrane components (e.g. receptors) accumulating in special domains of cell membranes. We analyze how certain variations in lateral diffusibility and solubility of the membrane would increase the efficiency of transport to these regions. A theorem is derived to show that the meantime of capture, t,, for particles diffusing to a trap from an annular region surrounding it, is intermediate to the t, values that correspond to the minimum and maximum diffusion coefficients that obtain in this region. An analytical solution for t, as a function of the gradient of diffusivity surrounding a trap is derived for circular geometry. Since local diffusion coefficients can be increased dramatically by reducing the concentration of intra-membrane particles and/or allowing them to form aggregates, such mechanisms could greatly enhance the diffusion-limited transport of particular membrane components to a trap (e.g. coated pit). If the trap is surrounded by an annular region in which the probe particles' partition function is increased, say, by the local segregation of certain phospholipids, t, is shown to vary inversely with the logarithm of the relative partition function. We provide some conjectural examples to illustrate the magnitude of the effects which heterogeneities in diffusibility and solubility may have in biological membranes.