Inhibitors of efflux pumps

Pages JM, Masi M, Barbe J. Inhibitors of efflux pumps in Gram-negative bacteria. Trends Mol. Med. 2005 ll(8) 382-389. 

Pages, J.M., Masi, M., and Barbe, J. (2005) Inhibitors of efflux pumps in Gramnegative bacteria. Trends in Molecular Medicine, 11 (8), 382-389. 

The development of compounds able to selectively block or to inhibit the ATP-dependent transport function of these proteins is a very important issue for the improvement of the drug therapy, mainly in the fields of oral delivery, brain targeting and cancer therapy [71]. Oral bioavailability of drugs substrate of efflux pumps can be improved by co-administration of efflux pump inhibitors. In the case of cancer treatment, modulators of drug efflux pumps are not expected to kill multidrug resistant cells, but to restore the cytotoxic effect of coadministered anticancer agents. The modulators or inhibitors of efflux pumps can be categorized into... 

Additional factors that will affect the breadth of spectrum of an antimicrobial inhibitor cannot be predicted at present from genome information alone. Among these factors, efflux transporters may modulate the species specificity of numerous antimicrobial agents [56,57], While many classes of efflux pumps can be recognized from sequence homology [56], no prediction of the compounds that will be subject to efflux currently can be derived from sequence information. 

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. 

In summary it can be said that there are a lot of possibilities available to overcome the efflux pump-mediated absorption barrier in the intestinal tract. Further, more selective or more potent inhibitors will follow but it has to be carefully decided for each drug or therapy which type or class of inhibitor or efflux pump modulator might be best suited. Also drug delivery systems combining different efflux pump modulating properties have to be investigated in the future. 

Lomovskaya O, Bostian KA. Practical applications and feasibility of efflux pump inhibitors in the clinic—a vision for applied use. Biochem. Pharmacol. 2006 71(7) 910-918. 

O., Watkins, W.J., Ohta, T., Nakayama, K., and Ishida, Y. (2003) Conformationally-restricted analogues of efflux pump inhibitors that potentiate the activity of levofloxacin in Pseudomonas aeruginosa. Bioorganic Medicinal Chemistry Letters, 13 (16), 2755-2758. 

Breast Cancer Resistance Protein (BCRP, also known as MXR or ABCP), first cloned from mitoxantrone and anthracycline-resistant breast and colon cancer cells [188, 189] is a half-transporter efflux pump believed to function as a homo-or hetero-dimer. Following its identification, BCRP-mediated drug resistance was observed for topoisomerase inhibitors including camptothecins [190, 191] and in-dolocarbazoles [192]. In normal tissues, BCRP was detected in placental syncytio-trophoblasts, hepatocyte canalicular membrane, apical intestinal epithelia and vascular endothelial cells [193]. These findings support the important role BCRP plays in modulating topotecan bioavailability, fetal exposure and hepatic elimination [194]. Considering that the substrates and tissue distributions for BCRP overlap somewhat with MDR1 and MRPs [195], additional studies will be required to define the relative contribution of each of these transporters in the overall and tis-... 

Verapamil/Digoxin Efflux pump sub-strate/inhibitor Co-administration of verapamil/digoxin can be used to demonstrate the impact of efflux transporters on permeability [134]... 

Ketoconazole Efflux pump modulator and/or CYP inhibitor Can be used to demonstrate the impact of intestinally mediated efflux/metabolism on permeability estimates [114]. 

There are several efflux pumps which may affect absorption, blood-brain-barrier penetration, and reabsorption from kidney microtubules. The most commonly tested efflux pump in early drug discovery is the P-glycoprotein. Assays to identify P-glycoprotein substrates or inhibitors can be run using a variety of cell lines. 

Cherigo L, Pereda-Miranda R, Fragoso-Serrano M, Jacobo-Herrera N, Kaatz GW, Gibbons S (2008) Inhibitors of Bacterial Multidrug Efflux Pumps from the Resin Glycosides of Ipomoea murucoides. J Nat Prod 71 1037... 

The most recent example of in silico efflux modeling has been based on Caco-2 permeability measured in the basal to apical direction [100]. This model can be very effective at ruling out compounds that most likely will show low in vivo intestinal absorption - however it carmot indicate which efflux pump(s) is/are responsible for that, making it more difficult for designers to circumvent the problem. Johnson [92] also included in his review an excellent summary of QSAR models and rules of thumb developed for P-gp substrates and inhibitors. These models are normally based on efflux ratios from MDCK/MDRl or Caco-2 cell lines - in the latter case it is important to notice that the data is combined with inhibition values from the calcein-AM assay, as the observed efflux might not be exclusively due to P-gp. 

The difluorocyclopropane motif is found in zusuquidar, an inhibitor of the efflux pump (Figure 8.10). 

Serai, C., et al. 2003. Influence of P-glycoprotein and MRP efflux pump inhibitors on the intracellular activity of azithromycin and ciprofloxacin in macrophages infected by Listeria monocytogenes or Staphylococcus aureus. J Antimicrob Chemother 51 1167. 

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