BCRP transporter

Zhang, Y., Gupta, A., Wang, H., et al. (2005) BCRP transports dipyridamole and is inhibited by calcium channel blockers. Pharm. Res. 22, 2023-2034. 

Houghton PJ, Germain GS, Harwood FC, Schuetz JD, Stewart CF, Buchdunger E, Traxler P (2004) Imatinib mesylate is a potent inhibitor of the ABCG2 (BCRP) transporter and reverses resistance to topotecan and SN-38 in vitro. Cancer Res 64, 2333— 2337. 

BCRP (ABCG2) The breast cancer resistance protein (BCRP) transporter is also known as mitoxantrone resistance (MXR) protein (Miyake et al., 1999 Krishnamurthy and Schuetz, 2006). BCRP is expressed in plasma membrane of placental syncytiotrophoblasts of the chorionic villus (Mao, 2008 Robey et al., 2009), mammary glands, testis, canicular membrane of hepatocytes, cortical and proximal tubules in the kidney, villous tip of intestinal cells in the small intestine, hematopoietic stem cells, endothelial cells of venules and capillaries, and the luminal surface of the endothelial cells at the blood-brain barrier. The substrate specificity for BCRP overlaps broadly with P-gp therefore, the clinical DDI implications for BCRP are as yet not well defined. The current limited data suggest that BCRP may have an impact on chemoresistance in cancer (Noguchi et al., 2009). Rosuvastatin and topotecan have been reported to increase plasma AUC for antivirals and cyclosporins (Allen et al., 2002 Maliepaard et al., 2001, Table 4.8). 

Most ABC-transporters, especially those located in the plasma membrane, are phosphorylated and glycosylated transmembrane proteins of different molecular weights (e.g., P-gp 170 kDa MRP2 190 kDa BCRP 72 kDa). Topologically, most ABC-transporter show a similar structure they are organized in two transmembrane domains (TMD), each consisting of six... 

The breast cancer resistance protein (BCRP) belongs to the G-branch of the ABC-transporter family (ABCG2). In contrast to most other ABC-proteins, BCRP consists of only one transmembrane domain (TDM) with one nucleotide binding fold (NBF) at its C-terminus. Because of this structural characteristic BCRP as well as other ABC-transporters with only one TMD are termed half transporters. To achieve functional activity these transporters have to form hetero- or homodimers. BCRP is involved in the multidrug resistance of certain tumors and transports endogenous compounds like cholesterol and steroid hormones. 

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... 

Importantly, the currently available transporter models only cover a small fraction of all transporters involved in drug disposition. Other than incorporating current stand-alone transporter models into systemic models to directly predict drug pharmacokinetic properties, continued efforts are still needed to investigate other transporters such as MRP, BCRP, NTCP, and OAT, to get a more complete understanding of the drug pharmacokinetic profile. 

The study of active transport mechanisms has grown substantially in recent years, with transport proteins such as P-gp, BCRP, and MRP-2 among the most studied [59]. Several types of in vitro assays to assess substrates of transporters have been established these include assays directed toward intestinal and biliary efflux [60]. Assays that measure passive and active transport are also used to assess penetration of the blood-brain barrier. In addition to the assays described above, transfected cell lines that overexpress transporters present in the blood-brain barrier are also employed [61]. 

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-... 

The role of other ABC-efHux transporters (ATP-binding cassette transporters) such as MRPs and BCRP was also intensively investigated over the past decade. However, most studies investigating the importance of ABC transporters for drug disposition were performed with different cell lines and animal models. In comparison to P-glycoprotein, only limited human data are available about the role of ABC transporters on drug disposition. In this chapter mainly human data will be discussed. For more detailed description and in vitro data about MRPs see Section 15.3. 

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... 

Merino G, Alvarez Al, Pulido MM, Molina AJ, Schinkel AH, Prieto JG (2006) Breast cancer resistance protein (BCRP/ABCG2) transports fluoroquinolone... 

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