Efflux transport system

The body has developed defense mechanisms that reduce the amount of foreign chemicals, such as drugs, that enter the body. One of the more prominent of these mechanisms is an efflux transport system that pumps some drugs back into the intestinal lumen following absorption into the enterocytes and that is responsible for the lack of complete absorption of some drugs. This efflux transport system is ... 

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

C) Plasmid-mediated changes in efflux transport system... 

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. 

Role of Drug Efflux Transport Systems in the Blood-Brain Barrier..604... 

Efflux systems of major importance in the intestinal epithelium are P-glycoprotein (P-gp) (Mizuno et al. 2003), multidrug resistance-associated protein 2 (MRP2) (Jansen et al. 1993), and breast cancer resistance protein (BCRP) (Doyle et al. 1998, Doyle and Ross 2003). The latter is described as a half-transporter and possibly functions as a homodimer (Schinkel and Jonker 2003). Details on the molecular weight, structure, substrates, and expression of P-gp, MRP2, and BCRP are listed in Table 3.2. It needs to be mentioned that expression of these intestinal efflux transporter systems shows high... 

In this review efflux pump inhibitors are classified into two groups low molecular mass inhibitors and polymeric inhibitors, because the high molecular mass of the polymeric excipients prevents absorption into systemic circulation after oral administration. In some cases, just a local inhibition of efflux transporters in the intestine is desired, whereas in other cases also an additional systemic modulation of efflux pumps can be of advantage. For chronical treatments, impact on the complex systemic efflux transporter system can result in severe complications. In this case, an enhanced intestinal absorption of efflux pump substrates can be achieved by using drug delivery systems based on polymeric inhibitors. On the other hand, in cancer therapy it would be of advantage to reduce efflux of anticancer compounds also in the systemic system because tumour tissues often overexpress these transporters. Then a low molecular mass efflux inhibitor could be useful. 

Kusuhara H, Sugiyama Y. 2001. Efflux transport systems for drugs at the blood-brain barrier and blood-cerebrospinal fluid barrier. Part 1. Drug Discov. Today 6(3) 150-56... 

Figure 3.2. Potential mechanisms for drug movement across the blood-brain barrier. Routes of passage include passive diffusion through the brain capillary endothelial cells (A) utilization of inwardly directed (i.e. towards brain) transport or carrier systems expressed on brain capillary endothelial cells (B) utilization of outwardly directed (i.e. towards blood) efflux transport systems (C) or inclusion in various endocytic vesicular transport processes occurring within the brain capillary endothelial cells (D).

Kusuhara, H., and Sugiyama, Y. (2004) Efflux transport systems for organic... 

Kusuhara H, Sugiyama Y. Efflux transport systems for organic anions and cations al the blood-CSF barrier. Adv Drug Deliv Rev 2004 56(12) 1741-1763. 

ArsA is a membrane-associated ATPase (see Fig. 3) (45,46) attached to the ArsB inner-membrane protein (30,47) and energizing the arsenite efflux pump by ATP hydrolysis (33,39). Such alternative energy coupling is unique among known bacterial uptake or efflux transport systems. To date, all other systems that have been studied are either membrane potential-driven or ATP-driven transporters. The ArsAB pump is the only one that can be converted from one form of energy coupling to the other by addition or removal of genes. This is a natural phenomenon (8) and also can be reconstructed in laboratory studies (33). 

Figure 3 Schematic presenting multiple effects of Pluronic block copolymers displayed in MDR ceU. These effects include (a) decrease in membrane viscosity ( fluidization ) (b) ATP depletion (c,d) inhibition of drug efflux transport systems (e) reduction in GSH/GST detoxification activity and (f) drug release from acidic vesicles in the cell. Effects of Pluronic block copolymers on apoptosis (g) are not sufficiently studied at present. (From Ref. 94.)...

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