Active efflux

The second general mechanism to cause resistance to antibacterial agents is to prevent the drug from reaching its target site. This is either achieved by altered rates of entry (reduced uptake) or by the active removal of the dtug (active efflux) [4]. 

Isken S, JAM de Bont (1996) Active efflux of toluene in a solvent-resistant bacterium. J Bacterial 178 6056-6058. 

Carrier-mediated transport, Active Efflux, Passive (trans and para cellular) diffusion... 

Table 18.2 lists 30 of the molecules used in this study that are known to be substrates for active transport or active efflux. The mechanistic ACAT model was modified to accommodate saturable uptake and saturable efflux using standard Michaelis-Menten equations. It was assumed that enzymes responsible for active uptake of drug molecules from the lumen and active efflux from the enterocytes to the lumen were homogeneously dispersed within each luminal compartment and each corresponding enterocyte compartment, respectively. Equation (5) is the overall mass balance for drug in the enterocyte compartment lining the intestinal wall. 

Cross-resistance to [Ru(r 6-bip)Cl(en)]PF6 in A2780ad fell from a factor of 38 to only threefold upon co-administration of verapamil, indicating that P-glycoprotein mediated active efflux of the anticancer drug was predominantly responsible for the observed cross-resistance and could be abrogated by addition of the competitive inhibitor. Such behavior is common for lipophilic positively charged drugs. 

In order for allelochemicals to enter the body of a herbivore, absorption must occur across the gut lining. Curtailing the initial absorption of dietary allelochemicals may be a herbivore s first line of defense against plant toxins. Studies have citied the lack of absorption or metabolism of lipophilic plant secondary metabolites (i.e., terpenes), conducive to phase I or II detoxification, in the gut of terrestrial herbivores rather these compounds are excreted unchanged in the feces (Marsh et al. 2006b). While physical barriers or surfactants have been used to explain this limited adsorption in both marine and terrestrial herbivores (Lehane 1997 Barbehenn and Martin 1998 Barbehenn 2001 for review of marine herbivores, see Targett and Arnold 2001), active efflux of plant allelochemicals out of enterocytes into the gut lumen has received limited attention until now. 

Chu, X.Y., Suzuki, H Ueda, K., Kato, Y Akiyama, S. and Sugiyama, Y. (1999) Active efflux of CPT-11 and its metabolites in human KB-derived cell lines. Journal of Pharmacology and Experimental Therapeutics, 288, 735-741. 

In the transport assays, the permeability of a compound in both absorption and secretion directions is measured using polarized epithelial cells that constitutively express high levels of P-gp (e.g. Caco-2) or have been transfected with the gene for a specific P-gp (e.g. MDR1-transfected MDCK or LLC-PK1 cells). Since P-gp is expressed on the apical membrane, ratios ofbasolateral-to-apical (B —> A) permeability versus apical-to-basolateral (A —> B) permeability greater than 1 may indicate an active efflux transport process. Bidirectional permeability measurements can also be performed in the presence of a specific P-gp inhibitor. Thus, apical-to-basolateral permeability increases and basolateral-to-apical permeability decreases such that... 

Decreased production or mutation of TOPO-1 can cause resistance to the cytotoxic effects of topotecan and other CPTs active efflux of TPT by P-glycoprotein-mediated transport might also contribute to resistance. 

Important limitations of the PBPK approach are realized for class 3 and 4 compounds with significant active distribution/absorption processes, where biliary elimination is a major component of the elimination process or where the assumptions of flow-limited distribution and well mixed compartments are not valid and permeability-limited distribution is apparent. These drawbacks could be addressed by the addition of permeability barriers for some tissues and by the incorporation of a more complex liver model which addresses active uptake into the liver, active efflux into the bile, biliary elimination and enterohepatic recirculation. However, this improvement to current methodologies requires the availability of the appropriate input data for quantification of the various processes involved as well as validation of the corresponding in vitro to in vivo scaling approaches. 

In principle there is no cross-resistance among the individual vinca alkaloids. However cells which are multidrug-resistant due to an activated efflux pump may display cross-resistance to vinca alkaloids, the epipodophyllotoxins, anthracyclines. 

Active efflux transporters also exist in the placenta, analogous to the gut and blood-brain barrier. These are Pgp, multidrug resistance-associated protein (MRP), and breast cancer resistance protein (BCRP). These transport proteins are located in many tissues but also appear to be expressed in the placenta. Though the substrate specificities of these proteins have not been completely described, they appear to function as efflux transporters, moving endogenous and exogenous chemicals from the placental cells back to the systemic circulation. In this way, they serve as a mechanism to protect the fetus from exposure to unintended chemicals. 

Resistance to the sulfonamides can be the result of decreased bacterial permeability to the drug, increased production of PABA, or production of an altered dihydropteroate synthetase that exhibits low affinity for sulfonamides. The latter mechanism of resistance is plasmid mediated. Active efflux of the sulfonamides has also been reported to play a role in resistance. The inhibitory effect of the sulfonamides also can be reversed by the presence of pus, tissue fluids, and drugs that contain releasable PABA. 

D) Changes in DNA gyrases and active efflux transport system resulting in decreased permeability of drug. 

B. Humans cannot synthesize folic acid (A) diet is their main source. Sulfonamides selectively inhibit microbially synthesized folic acid. Incorporation (B) of PABA into microbial folic acid is competitively inhibited by sulfonamides. The TMP-SMX combination is synergistic because it acts at different steps in microbial folic acid synthesis. All sulfonamides are bacteriostatic. Inhibition of the transpeptidation reaction (C) involved in the synthesis of the bacterial cell wall is the basic mechanism of action of (3-lac-tam antibiotics Changes in DNA gyrases (D) and active efflux transport system are mechanisms for resistance to quinolones. Structural changes (E) in dihydropteroate synthetase and overproduction of PABA are mechanisms of resistance to the sulfonamides. 

B. Overproduction (A) of PABA is one of the resistance mechanisms of sulfonamides. Changes in the synthesis of DNA gyrases (B) is a well-described mechanism for quinolone resistance. Plasmid-mediated resistance (C) does not occur with quinolones. An active efflux system for transport of drug out of the cell has been described for quinolone resistance, but it is not plasmid mediated. Inhibition of structural blocks (D) in bacterial cell wall synthesis is a basic mechanism of action of p-lactam antibiotics. Inhibition of folic acid synthesis (E) by blocking different steps is the basic mechanism of action of sulfonamides. 

Nikaido H. Prevention of drug access to bacterial targets Permeability barriers and active efflux. Science 1994 264 382-388. 

Explosion of the compound from the cell usually through active efflux pumps... 

Active efflux pump removing antibiotic which passes into the cell. 

Bugg, T., J. M. Focht, M. A. Pickard, and M. R. Gray, Uptake and active efflux of polycyclic aromatic hydrocarbons by Pseudomonas fluorescens LP6a , Appl. Environ. Microbiol., 66, 5387-5392 (2000). 

Thus, at least four different mechanisms have been established for the exclusion of Ca2+ by bacterial cells, namely, active efflux of Ca2+ via the Ca2+/H+ antiport (E. coli, Azotobacter vinelandii and Mycobacterium phlei), the Ca2+/Na+ antiport (H. halobium), via the hydrolysis of ATP (S. faecalis), and calcium-phosphate symport (E. coli). 

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