Efflux pumps intestine

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-... 

Its target genes regulate the secretion of bile acids and phospholipids into bile (bile salt efflux pump, MDR2 and 3), the intestinal reabsorption of bile add (ileal bile... 

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

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. 

Permeation enhancement by excipients has generated some interest, but there is still much research that needs to be done to elucidate the mechanism of these excipients. PEG-400 (and many other excipients such as polyethylene glycol, poloxamers, polysorbates, and vitamin E) is known to inhibit p-glycoprotein, which may increase the bioavailability of the API, which was a substrate for this efflux pump. On the other hand, it has been demonstrated that PEG-400 can accelerate small intestinal transit, and thereby reduce the bioavailability of some drugs (e.g., ranitidine) (5). 

Beside membrane transporters such as PepTl and PepT2, which act as absorptive systems, there are transporters like P-gp and the MRP 15, which transport certain drugs actively back into the intestinal lumen. These efflux pumps are located in several tissues including liver, kidney, brain, and intestine [90,91]. In the intestine, efflux systems are predominantly located at the apical side of the epithelial cells. Lipophilic drugs are usually absorbed by the transcellular route so that they are mostly affected by these systems. Interestingly, the intracellular occurring CYP3A metabolizes compounds to substrates that are eliminated by P-gp [92],... 

FIGURE 6.1 The barriers that a lipophilic drug has to transverse along the intestinal absorption process (1) dissolution and solubilization in the intestinal milieu, (2) narrow absorption window, (3) unstirred water layer, (4) efflux pumps, (5) intra-enterocyte metabolism, and (6) first pass hepatic metabolism. 

Whereas some transporters located in the apical wall of the enterocyte facilitate absorption, there are others that serve as efflux transporters. These are considered as the multiple drug resistance (MDR) transporters, and they play a major role in the disposition of many drugs. The most extensively studied MDR transporter is the apical P-glycoprotein (P-gp) efflux pump that reduces the fraction of drug absorbed by transporting the drug from the enterocyte back to the intestinal lumen [6]. 

Inhibition of these efflux pumps by various compounds can lead to enhanced absorption of several drugs across the intestine. 

It has been previously reported that inhibition of efflux pumps by various compounds can lead to enhanced absorption of drugs across the intestine (Kim 2002). P-gp can be inhibited by a range of substances that blocks its function either by acting as a high avidity substrate, like verapamil, diltiazem or cyclosporine (Gerrard et al. 2004), or by binding to it such as sulphydryl-substituted purines (Al-Shawi et al. 1994). 

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. 

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). 

Bypassing intestinal transmembrane transporters mainly by a paracellular absorption would avoid or limit exposure of the substrate to these efflux pumps. Improved paracellular uptake can be achieved by using fatty acids, calcium chelators such as EDTA, papain, bromelain, surfactants, chitosans, polyacrylic acid or thiolated polymers. 

Therefore, increased bioavailability could be reached by using bioadhesive drug delivery systems, releasing the drug in the upper part of the small intestine where efflux pump activity is lower. 

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. 

Grabovac V., Bernkop-Schnurch A. (2006) Thiolated polymers as effective inhibitors of intestinal Mrp2 efflux pump transporters. Sci Pharm, 74. 

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