Efflux pump inhibitor

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. 

In this chapter, several efflux pump inhibitors such as low molecular mass inhibitors, polymeric inhibitors and advanced formulation approaches on how to overcome drug efflux are discussed. 

Strategies to Overcome Efflux Pumps 7.2.1 Efflux Pump Inhibitors... 

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. 

Based on the specificity and affinity, low molecular mass efflux pump inhibitors are classified into three generations (Werle 2008a). First-generation P-gp inhibitors such as verapamil or cyclosporine are compounds that are in clinical use for other indications and exhibit additional inhibitory properties. 

In a patent by Carreno-Gomez and Duncan, the use of polysaccharides and dendrimers as efflux pump inhibitors for the oral delivery of antitumour,... 

This strategy is very interesting because prodrug modification would avoid the need of additionally administered efflux pump inhibitors. 

Werle M. (2008a) Polymeric and low molecular mass efflux pump inhibitors for oral drug delivery. J Pharm Sci, 97, (1), 60-70. 

Strategies to overcome the absorption barrier focus on the other hand on low molecular mass permeation enhancers (Chapter 5) such as medium chain fatty acids, which can still be regarded as a kind of gold standard. As low molecular mass permeation enhancers are per se rapidly uptaken from the gastrointestinal mucosa, however, the macromolecular drug is to a considerable high extent left alone behind in the gastrointestinal tract. In addition, local and systemic toxic side effects of low molecular mass permeation enhancers cannot be excluded. In contrast, polymeric permeation enhancers (Chapter 6) are simply too big to be absorbed from the GI tract. Consequently, systemic toxic side effects can be excluded. More recently various excipients could be identified as potent efflux pump inhibitors which can be subdivided into low molecular mass efflux pump inhibitors and polymeric efflux pump inhibitors (Chapter 7). Certain polymeric... 

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. 

Fox E, Bates SE (2007) Tariquidar (XR9576) a P-glycoprotein drug efflux pump inhibitor. Expert Rev Anticancer Ther 7(4) 447 59... 

For the above reasons, a dramatic reduction in the emergence of fluoroquinolone (ciprofloxacin) resistance is seen when bacterial strains lacking efflux pumps are used for resistance selection or when selection experiments are performed in the presence of an efflux pump inhibitor (EPI) [133-136], the opposite of what is seen clinically. 

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. 

Schumacher, A., Steinke, P., Bohnert. J.A., Akova, M., Jonas, D., and Kern, W.V. (2006) Effect of l-(l-naphthylmethyl)-piperazine, a novel putative efflux pump inhibitor, on antimicrobial drug susceptibility in clinical isolates of Enterobacteriaceae other than Escherichia coli. The Journal of Antimicrobial Chemotherapy, 57 (2), 344—348. 

Nakayama, K., Ishida, Y, Ohtsuka, M., Kawato, H., Yoshida, K., Yokomizo, Y, Hosono, S., Ohta, T, Hoshino, K, Ishida, H., Renau, T.E., Leger, R., Zhang, J.Z., Lee. V.J.. and Watkins, W.J. (2003) MexAB-OprM-specific efflux pump inhibitors in Pseudomonas aeru nosa. Part 1. Discovery and early strategies for lead optimization. Bioorganic Medicinal Chemistry Letters, 13 (23). 4201-4204. 

Stavri, M., Piddock, L.J., and Gibbons, S. (2007) Bacterial efflux pump inhibitors fiom natural sources. The Journal of Antimicrobial Chemotherapy, 59 (6), 1247-1260. 

Bernkop-Schnurch, A. and Grabovac, V. (2006) Polymeric efflux pump inhibitors in oral drug delivery. Am. J. Drug Deliv., 4, 263-272. 

Approaches to stabilize or avoid instability Prodrugs Enteric coating (protection in stomach) Lipid vehicles (micelles or emulsions/microemulsions) Enzyme inhibitor Lymphatic delivery (to avoid first-pass metabolism) Lipid prodrugs P-gp efflux pump inhibitors ... 

Amphiphilic Block Copolymers Potent Efflux Pump Inhibitors for Drug Delivery AND Cancer Therapy... 

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