Membranes drug transport

Mechanisms Vinblastine and vincristine are spindle poisons which, by preventing the assembly of tubulin dimers into microtubules, block the formation of the mitotic spindle. They act primarily in the M phase of the cancer cell cycle. Resistance may occur from increased efflux of the drugs from tumor cells via the membrane drug transporter. 

Glycosteroids in vesicles and liposomes, interactions with membranes, drug transport and solubilization... 

Permeation of a drug through biological membranes against the electrochemical gradient. This type of drug transport requires energy produced by intracellular metabolic processes. 

VMATs are not inhibited by drugs such as cocaine, tricyclic antidqnessants and selective serotonin reuptake inhibitors that affect plasma membrane monoamine transport. Amphetamines have relatively selective effects on monoaminergic cells due to selective uptake by plasma membrane monoamine transporters, but their effect appears to be mediated by their ability as weak bases to reduce ApH, the driving force for vesicular monoamine transport that leads to efflux of the vesicular contents into the cytoplasm. 

Figure 20.1 Schematic diagram illustrating how antidepressants increase the concentration of extraneuronal neurotransmitter (noradrenaline and/or 5-HT). In the absence of drug (b), monoamine oxidase on the outer membrane of mitochondria metabolises cytoplasmic neurotransmitter and limits its concentration. Also, transmitter released by exocytosis is sequestered from the extracellular space by the membrane-bound transporters which limit the concentration of extraneuronal transmitter. In the presence of a MAO inhibitor (a), the concentration of cytoplasmic transmitter increases, causing a secondary increase in the vesicular pool of transmitter (illustrated by the increase in the size of the vesicle core). As a consequence, exocytotic release of transmitter is increased. Blocking the inhibitory presynaptic autoreceptors would also increase transmitter release, as shown by the absence of this receptor in the figure. In the presence of a neuronal reuptake inhibitor (c), the membrane-bound transporter is inactivated and the clearance of transmitter from the synapse is diminished...

MAO has been inhibited. As a result, transmitter accumulates in the cytoplasm and is exported into the synapse via the membrane-bound transporter. The ensuing (impulse-independent) sympathetic arousal can be disastrous, culminating in a hypertensive crisis and stroke. Although this process is a pharmacological curiosity and certainly contributed to the demise of MAOIs, it is possibly overrated (Tyrer 1979) it has been estimated that the number of deaths associated with the use of the MAOI, tranylcypromine, amounts to only 1 per 14000 patient years. However, this sequence of events echoes exactly the acute actions of methylenedioxymethamphetamine (MDMA, Ecstasy ) and undoubtedly accounts for some of the deaths attributed to this drug. 

Camenisch, G., Folkers, G., Van de Waterbeemd, H. Comparison of passive drug transport through Caco-2 cells and artificial membranes. Int. J. Pharm. 1997, 147, 61-70. 

Stewart, B. H., Chan, O. H. Use of immobilized artifidal membrane chromatography for drug transport applications. /. Pharm. Sci. 1998, 87, 1471-1478. 

Permeability-pH profiles, log Pe - pH curves in arhficial membrane models (log Pjpp - pH in cehular models), generally have sigmoidal shape, similar to that of log Dod - pH cf. Fig. 3.1). However, one feature is unique to permeabihty profiles the upper horizontal part of the sigmoidal curves may be verhcally depressed, due to the drug transport resistance arising from the aqueous boundary layer (ABL) adjacent to the two sides of the membrane barrier. Hence, the true membrane contribution to transport may be obscured when water is the rate-limiting resistance to transport. This is especially true if sparingly soluble molecules are considered and if the solutions on either or both sides of the membrane barrier are poorly stirred (often a problem with 96-well microhter plate formats). 

When the pH is different on the two sides of the membrane, the transport of ioniz-able molecules can be dramatically altered. In effect, sink conditions can be created by pH gradients. Assay improvements can be achieved using such gradients between the donor and acceptor compartments of the permeation cell. A three-compartment diffusion differential equation can be derived that takes into account gradient pH conditions and membrane retention of the drug molecule (which clearly still exists—albeit lessened—in spite of the sink condition created). As before, one begins with two flux equations... 

Seydel, J. K. Coats, E. A. Cordes, H. P. Weise, M., Drug membrane interactions and the importance for drug transport, distribution, accumulation, efficacy and resistance, Arch. Pharm. (Weinheim) 327, 601-610 (1994). 

Various diffusion cell configurations have been used to investigate drug transport from ointments, creams, and gels through a membrane to an aqueous receptor phase. 

Thin-film transport cell (membrane method) Drug transport from thin films of topical dosage forms 24... 

In addition to the aforementioned effects on paracellular drug transport, Ca2+ also plays an important role in the transcytosis of macromolecules. The entry of the plant lectins abrin, modeccin, and viscumin into Vero cells was inhibited in a Ca2+-free medium a well as in a Ca2+-containing medium containing verapamil and Co2+, both inhibitors of Ca2+ [217], Ca2+ is therefore required at a stage after the binding of the above lectins, perhaps in the fusion and exocytosis of membrane vesicles. 

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