Efflux transporters BCRP

Both influx and efflux transporters are located in intestinal epithelial cells and can either increase or decrease oral absorption. Influx transporters such as human peptide transporter 1 (hPEPTl), apical sodium bile acid transporter (ASBT), and nucleoside transporters actively transport drugs that mimic their native substrates across the epithelial cell, whereas efflux transporters such as P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), and breast cancer resistance protein (BCRP) actively pump absorbed drugs back into the intestinal lumen. 

Breast cancer resistance protein (BCRP) is another ATP-dependent efflux transporter that confers resistance to a variety of anticancer agents, including... 

For other efflux transporters such as BCRP (ABCG2), human pharmacokinetic and pharmacodynamic data are currently rare. However, an investigation of the influence of polymorphisms in ABC-transporter genes on the accumulation of nelfinavir in peripheral blood mononuclear cells (PBMCs) revealed no associations between the polymorphisms in the transporters analyzed and the accumulation of nelfinavir in the PBMCs [151], A second study in patients clearly demonstrated an increase in the AUC of the orally and intravenously administered BCRP substrate topotecan when it is given with GF120918, an inhibitor of P-glycoprotein and BCRP [152],... 

Caco-2 Human colon adenocarcinoma Well-established cell model Differentiates spontaneously and expresses some relevant efflux transporters (e.g., P-gp, MRP1-2, BCRP) Interlaboratory differences... 

Active efflux transporters also exist in the placenta, analogous to the gut and blood-brain barrier. These are Pgp, multidrug resistance-associated protein (MRP), and breast cancer resistance protein (BCRP). These transport proteins are located in many tissues but also appear to be expressed in the placenta. Though the substrate specificities of these proteins have not been completely described, they appear to function as efflux transporters, moving endogenous and exogenous chemicals from the placental cells back to the systemic circulation. In this way, they serve as a mechanism to protect the fetus from exposure to unintended chemicals. 

Efflux systems of major importance in the intestinal epithelium are P-glycoprotein (P-gp) (Mizuno et al. 2003), multidrug resistance-associated protein 2 (MRP2) (Jansen et al. 1993), and breast cancer resistance protein (BCRP) (Doyle et al. 1998, Doyle and Ross 2003). The latter is described as a half-transporter and possibly functions as a homodimer (Schinkel and Jonker 2003). Details on the molecular weight, structure, substrates, and expression of P-gp, MRP2, and BCRP are listed in Table 3.2. It needs to be mentioned that expression of these intestinal efflux transporter systems shows high... 

Choudhuri, S., and Klaassen, C. D. Structure, function, expression, genomic organization, and single nucleotide polymorphisms of human ABCB1 (MDR1), ABCC (MRP), and ABCG2 (BCRP) efflux transporters. Int. J. Toxicol. 25, 231-259, 2006. 

Ieiri I, Suwannakul S, Maeda K, Uchimaru H, Hashimoto K, Kimura M, Fujino H, Hirano M, Kusuhara H, Irie S, Higuchi S, Sugiyama Y (2007) SLCOIBI (OATP1B1, an uptake transporter) and ABCG2 (BCRP, an efflux transporter) variant alleles and pharmacokinetics of pitavastatin in healthy volunteers. Clin Pharmacol Ther 82 541-547... 

Figure 18.1. Topology of efflux transporters MRP1, P-glycoprotein and BCRP (Reproduced with permission from ref. 3).

Englund, G. et al. (2007) Efflux transporters in ulcerative colitis decreased expression of BCRP (ABCG2) and Pgp (ABGBl). Inflammatory Boivel Diseases, 13 (3), 291-297. 

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