Drag efflux

Paulsen IT, Chen J, Nelson KE, Saier MEI Jr. Comparative genomics of microbial drag efflux systems. J. Mol. Microbiol. Biotechnol. 2001 3 145-150. 

Figure 47.3. Schematic illustrating twofold effects of Pluronic block copolymers witli intemiediate lipophilicity on Pgp and MRPs drag efflux system. Tliese effects include (a) decrease in membrane viscosity ( fluidization ) resulting in inliibition of Pgp and MRPs ATPase activity, and (b) ATP depletion in BMVEC. Extremely lipo-pliilic or hydi ophilic Plui onic block copolymers do not cross tire cel-lulai membranes and do not cause energy depletion in tire cells.

Loscher W, Potsclika H (2005a) Drug resistance in brain diseases and tlie role of drag efflux ri ansporters. Nat Rev Neurosci 6 591-602. 

Further work is needed to determine the real role of Msr, Mef, and Mre proteins in enhanced drag efflux. 

P-glycoprotein-mediated efflux is a potential source of pecuHarities in drag pharmacokinetics, such as non-Hnearity. This includes dose-dependent absorption, drug-drag interactions, intestinal secretion and limited access to the brain. Assays are in development to quantify the interaction between transporters and drugs. One of the first is a 96-weU plate assay for P-gp binding [33, 34] and an MDRl ATPase test [35]. 

Aszalos A, Ross DD. Biochemical and clinical aspects of efflux pump related resistance to anti-cancer drags. Anticancer Res 1998 18(4C) 2937-2944. 

In recent years, it has been found that the barrier function of the intestinal epithelium cannot be adequately described by a combination of metabolic and physical barriers alone. Apically polarized efflux systems are known to be present in cancer cells and represent a major barrier to the uptake of a wide variety of chemotherapeutic agents (i.e. in multi-drag resistance). Efflux systems have also now been identified in normal intestinal and colonic cells, and also at other epithelial sites. 

Recent studies have shown that p-glycoprotein is located in the astrocyte membranes (and not in the brain capillary endothelium as previously accepted) and that it functions by reducing the volume of distribution of the drug in the brain. Thus this efflux system, by restricting the transcellular flux of some molecules, may serve as a further barrier to drag delivery to the CNS. 

PURPOSE AND RATIONALE During the last 10 years many uptake transporters as well as efflux transporters have been discovered in the GI and especially in the small intestine. They allow uptake of ions, amino acids, peptides, nucleic acids, sugars, organic acids, vitamins, cofactors and nucleosides. On the other hand, efflux transporters ensure protection of the organism from unwanted pathogen or compound delivery. Subsequently, cellular systems have been used to study uptake in mechanistic studies in more detail. Additionally inhibition studies provide hints on potential drag-drug interactions. 

Drags are tested at 10 p,M concentration and in two directions (apical to basolateral (a-b) and basolateral to apical (b-a)). Monolayer efflux studies are conducted at 37 °C in a humidified incubator with shaking (90 rpm) for 60 min. Transendothelial electrical resistance is measured with an Endohm Meter (World Precision Instruments, New Haven, CT). Reference drags for paracellular transport (14C-mannitol), tran-scellular transport (3H-propranolol), and Pgp efflux (amprenavir) should be included in each experiment. Concentrations of 14C-mannitol and 3H-propranolol are measured by liquid scintiallation counting. Amprenavir is analyzed by cassette LC/MS/MS analysis along with the test drags. 

Mahar Doan et al. (2002) used the assay to classify 93 CNS and non-CNS drags. The CNS set of drugs had a 7-fold lower incidence of passive permeability values <150 nm/s compared with the non-CNS set. The majority of drugs (72 %) were not Pgp substrates. The CNS drug set had a 3-fold lower incidence of Pgp-mediate efflux than the non-CNS drug set. For CNS delivery, they concluded that drugs should ideally have an in vitro passive permeability >150 nm/s and not be a good (b-a/a-b ratio < 2.5) Pgp substrate. 

Takatsuka Y, Nikaido H. Threonine-978 in the transmembrane segment of the multidrag efflux pump AcrB of Escherichia coh is crucial for drag transport as a probable component of the proton relay network. J. Bacteriol. 2006 188 7284-7289. 

The shear or drag force at radius r = Orzilnr Az) which can be considered to be the momentum flow in to the cylindrical surfece of the shell. The net efflux of momentum is the difference between the magnitudes the momentum out and momentum in ... 

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