Effect of excipients on breast cancer resistance protein substrate uptake activity

Yamagata, Tetsuo; Kusuhara, Hiroyuki; Morishita, Mariko; Takayama, Kozo; Benameur, Hassan; Sugiyama, Yuichi

doi:10.1016/j.jconrel.2007.08.021

Cited by 99 publications

(56 citation statements)

References 14 publications

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“…Ranitidine is metabolized in the liver to N-oxide, desmethylranitidine and S-oxide metabolites by cytochrome P450, particularly CYP 2C19, CYP 1A2, CYP 2D6 and CYP 3A4/5 (32,33). Cytochrome P450 enzymes are present in the gut wall enterocytes, as well as in the liver (23), and gender differences are noted with cytochrome P450 with women having higher CYP3A metabolism than men. These are attributed to the regulation of their expression and activity, probably due to hormonal influences rather than inherent differences based on allele variations.…”

Section: Male Volunteersmentioning

confidence: 99%

Polyethylene Glycol 400 Enhances the Bioavailability of a BCS Class III Drug (Ranitidine) in Male Subjects but Not Females

2008

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All doses of PEG 400 enhanced the bioavailability of ranitidine in male subjects but not females, with the most pronounced effect in males noted with the 0.75 g dose of PEG 400 (63% increase in bioavailability compared to control, p < 0.05). These findings have significant implications for the use of PEG 400 in drug development and also highlight the importance of gender studies in pharmacokinetics.

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Section: Male Volunteersmentioning

confidence: 99%

Polyethylene Glycol 400 Enhances the Bioavailability of a BCS Class III Drug (Ranitidine) in Male Subjects but Not Females

2008

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“…Pluronic P85 has been shown to inhibit both P-gp and MRP-mediated efflux of their substrates (Batrakova et al, 2001b(Batrakova et al, , 2003. Recent studies have indicated that Pluronic P85 inhibits the BCRP-mediated transport of mitoxantrone and topotecan (Yamagata et al, 2007). Use of inhibitor molecules, such as those listed above, to modulate transporter-mediated efflux may be valuable to improve the targeted bioavailability of substrates to the target sites (Fig.…”

mentioning

confidence: 99%

Substrate-Dependent Breast Cancer Resistance Protein (Bcrp1/Abcg2)-Mediated Interactions: Consideration of Multiple Binding Sites in in Vitro Assay Design

Giri¹,

Agarwal

Shaik

et al. 2008

Drug Metab Dispos

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ABSTRACT:In vitro assays are frequently used for the screening of substrates and inhibitors of transporter-mediated efflux. Examining directional flux across Madin-Darby canine kidney (MDCK) II cell monolayers that overexpress a transporter protein is particularly useful in identifying whether or not a candidate compound is an inhibitor or substrate for that transport system. Studies that use a single substrate or inhibitor in competition assays can be challenging to interpret because of the possible multiple mechanisms involved in substrate/inhibitor-protein interactions. During our previous studies of substrate-inhibitor-transporter interactions, we observed differences in breast cancer resistance protein (BCRP) inhibition, depending on the substrate and the inhibitor. Therefore, we investigated BCRP-mediated interactions with a 4 ؋ 4 matrix of substrates and inhibitors using monolayers formed from MDCKII cells transfected with murine BCRP (Bcrp1/Abcg2). The selective BCRP inhibitor 3-(6-isobutyl- Multidrug resistance observed in cancer therapy is commonly attributed to ATP-binding cassette (ABC) efflux transporter proteins, such as P-glycoprotein (P-gp), multidrug resistance-associated proteins (MRPs), and breast cancer resistance protein (BCRP). These ABC transport proteins are localized not only in drug-resistant cancer cells, but also in the plasma membranes of epithelial cells in various normal tissues such as intestine, liver, kidney, placenta, and the blood-brain barrier where they can influence absorption, distribution, metabolism, and excretion of their substrates (Leslie et al., 2005). The efflux transport protein BCRP is expressed in various organs, and because of its transmembrane orientation, this transporter is able to extrude substrates out of the cell (Maliepaard et al., 2001). BCRP is considered a half-transporter because of the presence of only six transmembrane domains, and it has been shown to exist in a multisubunit oligomeric structure that may be critical for its function (Bhatia et al., 2005).Numerous in vitro studies have characterized substrate-transporter interactions and these effects have also been observed in vivo (Merino et al., 2006;Shaik et al., 2007). Interaction of BCRP with various substrate molecules in vitro and in vivo has provided evidence that BCRP-mediated efflux could play a major role in the absorption, distribution, metabolism, and excretion of its substrate molecules (Staud and Pavek, 2005). Identifying inhibitors that modulate BCRPmediated efflux of substrates could be valuable in enhancing target exposure to the drug. Various molecules have been shown to have inhibitory effects on BCRP-mediated transport of its substrates. GF120918 is a potent P-gp inhibitor that was shown to also have an inhibitory effect on BCRP-mediated transport. For instance, GF120918 inhibits BCRP-mediated transport of abacavir, zidovudine, STI-571 (imatinib), and prazosin (Breedveld et al., 2005;Ejendal and Hrycyna, 2005;Pan et al., 2007). Fumitremorgin C was identified as the first select...

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“…It has also been shown that conjugation of negatively charged nanoparticles to glutathione led to nanoparticle efflux from the cell via MRP-transporters Holpuch et al, 2011). Some excipients are also potent ABC transporter inhibitors (Yamagata et al, 2007) and may be used in novel formulations to further improve PC bioavailability and targeted tissue distribution.…”

Section: Improving the Bioavailability Of Pcsmentioning

confidence: 99%

Oral Bioavailability and Disposition of Phytochemicals

Li¹,

Paxton²

2011

Phytochemicals - Bioactivities and Impact on Health

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Effect of excipients on breast cancer resistance protein substrate uptake activity

Cited by 99 publications

References 14 publications

Polyethylene Glycol 400 Enhances the Bioavailability of a BCS Class III Drug (Ranitidine) in Male Subjects but Not Females

Polyethylene Glycol 400 Enhances the Bioavailability of a BCS Class III Drug (Ranitidine) in Male Subjects but Not Females

Substrate-Dependent Breast Cancer Resistance Protein (Bcrp1/Abcg2)-Mediated Interactions: Consideration of Multiple Binding Sites in in Vitro Assay Design

Oral Bioavailability and Disposition of Phytochemicals

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