Efflux pump inhibition

Efflux Pump Inhibition to Improve Oral Bioavailability.99... 

PEG 300 on paclitaxel transport was observed. It was concluded that the efflux pump inhibition mechanism of PEG 300 was mediated by changes in the microenvironment of Caco-2 cell membranes (Hugger et al. 2002). These changes are probably related to modifications in the fluidity of the polar head group regions of cell membranes. 

The polysorbates used most regarding efflux pump inhibition are polyoxyethylene sorbitan monolaurates (Tween 20), polyoxyethylene sorbitan monopalmi-tates (Tween 40) and polyoxyethylene sorbitan monooleates (Tween 80). Various studies demonstrate the ability of polysorbates to inhibit efflux pumps. In transport experiments across intestinal mucosa, the efflux ratio (basolateral to apical drug transport/apical to basolateral drug transport) of rhodamine 123 was reduced in the presence of Tween 80 (Shono et al. 2004). In another study, Zhang et al. demonstrated enhanced absorption of the P-glycoprotein substrate digoxin in rats in the presence of Tween 80 (Zhang et al. 2003). 

Thiomers Mucoadhesive, permeation enhancing, enzyme inhibiting, efflux pump inhibiting Bernkop-Schnurch et al. (2004), Werle (2008) and Palmberger et al. (2008)... 

Further, the enhanced transport of the P-gp substrate acyclovir across excised rat intestinal mucosa and Caco-2 monolayers in the presence of thiolated chitosan was found to be due to efflux pump inhibition (Palmberger et al. 2008). Co-administration of paclitaxel and thiolated polycarbophil significantly improved paclitaxel plasma levels and led to a more constant pharmacokinetic profile and reduced tumour growth in mammary cancer-induced rats (Foger et al. 2008). 

Kaatz, G.W. (2005) Bacterial efflux pump inhibition. Current Opinion in Investigational Drugs, 6 (2), 191-198. 

The ability of amphiphilic block copolymers to modulate multi drag resistance related processes has been demonstrated the first time more than 10 years ago. Nowadays, the efflux pump inhibitory activity of amphiphilic block copolymers is used in two main areas. First, to improve the transport of efflux pump substrates across the blood brain barrier (BBB) and second, in cancer therapy. It has been shown that in the presence of amphiphilic block copolymers higher concentrations of certain anhcancer drugs, which are known as efflux pump substrates, can be found in the brain. Within the current chapter, recent developments in the field of amphiphilic block copolymer mediated efflux pump inhibition are discussed. Besides presenting data from in vitro and vivo studies, also the mechanisms involved in efflux pump inhibition are addressed. In addition, the influence of hydrophilicity/lipophilicity of various amphiphilic block copolymers as well as factors such as micelle formation on the efflux pump inhibitory activity are explained. 

Another important factor which is not directly related to the hydrophilicity/lipophilicity ratio of various pluronics but which strongly influences the efflux pump inhibitoiy activity of pluronics is micelle formation. Above a certain concentration, the so called critical micelle concentration (CMC), amphiphilic block copolymers self assemble into micelles. It has been demonstrated, that the efflux pump inhibitory activity of pluronics increases with increasing pluronie concentrations, but only until the CMC is reached. Above the CMC, substrate accumulation in cancer cells could not be further increased or was found to even decrease [37]. Therefore, the occurrence of pluronie unimers can be regarded as the crucial prerequisite for the efflux pump inhibitory activity of pluronics [37]. As one mechanism for efflux pump inhibition has been identified to be ATP depletion, it seems necessary that the pluronie unimers are transported into the cells in order to exert this action. 

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