Commonly, physicochemical properties of polymers and release mechanism for polymer compositions were considered in designing any formulation. However, several excipients especially polymers have shown pharmacological interaction with physiological components such as membrane situated efflux pumps. Such interactions could lead to altered drug bioavailability. Membrane situated efflux pump inhibitors were generally preferred to increase the substrate drug concentration inside the cell. These inhibitors are classified majorly into two groups: polymeric inhibitors and small molecule inhibitors (SMIHs). SMIHs include first, second and third generation agents. First generation SMIHs, such as quinine and verapamil have been majorly preferred in several disorders because of their pharmacological activity in addition to efflux pump inhibitory property (Beck et al., 1988; Tsuruo et al., 1981). Second and third generation SMIHs have been specifically developed to inhibit efflux pump along with circumvention of pharmacological interactions associated with first generation SMIHs (Woo et al., 2003; Asperen et al., 1997; Bardelmeijer et al., 2000). However, SMIH mediated risk of accumulation, toxicity and anti-targeting cannot be completely ignored. Hence, to overcome pharmacological interactions associated with actives, several pharmacologically inactive compounds have been successfully investigated for efflux pump inhibitory activity. These inactives include polymeric materials like Tween 80 and pluronic 85 (Friche et al., 1990; Alakhov et al., 1996).
A number of polymers are known to interact with membrane components that alter membrane transportability of several drugs. This is more useful in cancer treatment, where polymers inhibit membrane situated efflux pumps to improve drug delivery inside the cell. A thorough understanding of the interaction between polymeric inhibitors and efflux pump is very essential for developing better polymeric inhibitors with higher safety, efficacy and specificity. It has been reported that polymeric inhibitors may interact with or inhibit efflux pumps in several ways such as [a] bypassing of drug efflux system by drug-polymer conjugate (dendrimers); [b] inhibitor from conjugates with ATP that results into ATP depletion [poloxamer unimers (Batrakova et al., 2001b), Myrj, Brij, dendrimers]; [c] inhibitors interfering with ATP-binding sites resulting in site depletion for ATP binding [TPGS 1000 (Collnot et al., 2007), dendrimers]; [d] blockage of trans-membrane situated drug glp-1 receptor by polymeric inhibitor (thiomers) (Bernkop-Schnurch and Grabovac, 2006); [e] interactions between membrane and polymeric inhibitor that alter the integrity of membrane lipids [polyethylene glycol (PEG), thiomers, pluronics (Batrakova et al., 2001b), Myrj, Brij, dendrimers]. Jette et al. (1998) have reported that SMIHs usually inhibit the efflux pump by either modifying or completely blocking efflux pump-drug binding sites. In previous studies, several polymeric compounds with structural variations have been established for their efflux pump inhibitory activity.
It has been observed that different membrane transporters are continuously involved in the transport of materials across the biological membranes. Juliano and Ling (1976) have identified a membrane glycoprotein responsible for drug resistance in colchicin drug resistant cells and specified it as “P-glycoprotein”. Nature, localization and mechanisms of such transporters have been previously discussed independently by Thiebaut et al. (1987) and Cordon-Cardo et al. (1990). Additionally, the role of such transporter proteins in drug development and drug delivery has been discussed earlier by several researchers (Girardin, 2006; Majumdar et al., 2004; Varma et al., 2006). P-glycoprotein (PGP) is a transporter protein located in apical membranes of epithelial cells which acts as an efflux pump. It has been reported that these ATP dependent transporter proteins are capable of transporting actively several structurally diverse compounds outside cell, such as anticancer agents (Tsuji, 1998), immunosuppressants (Goldberg et al., 1988), steroid hormones (Yang et al., 1989), calcium channel blockers (Yusa and Tsuruo, 1989), beta-adrenoreceptor blockers and cardiac glycosides (Karlsson et al., 1993; Lannoy and Silverman, 1992). Cancer cell shows resistance to multiple drugs (multidrug resistant cell) due to over expression of such transporter proteins acting as efflux pumps. Additionally, these transporter proteins are also present in healthy tissues, such as the kidney, placenta, liver, brain, testis and intestine (Thiebaut et al., 1987; Cordon-Cardo et al., 1990). Leveque and Jehl (1995) have reported that these transporter proteins take part in the detoxification process in addition to other mechanisms where they influence pharmacokinetic processes. Choudhuri and Klaassen (2006) have identified breast cancer resistant proteins and multidrug resistant proteins (MRPs) 1 and 2 acting as efflux pumps in the same way as PGP. Therefore, the inhibition of efflux pump is a very essential step to enhance the transport of anticancer agents (efflux pump substrates) into multidrug resistant cells and improve drug delivery. This is a prerequisite in cancerous cells where the presence of an abundant number of efflux pumps (PGPs) results in lowered concentrations of anticancer drugs inside multidrug resistant cells and hence, therapeutic efficiency of such drugs get reduced or diminished totally.