Characterization of Substrates and Inhibitors for the In Vitro Assessment of Bcrp Mediated Drug–Drug Interactions

Muenster, Uwe; Grieshop, Birgit; Ickenroth, Karsten; Gnoth, Mark Jean

doi:10.1007/s11095-008-9632-1

Cited by 71 publications

(64 citation statements)

References 30 publications

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“…With use of mouse bcrp1-transfected cells, Ko143 gave a dose-dependent increase in Hoechst 33342 accumulation with an IC 50 of 0.15 M, similar to the previously reported values for bcrp inhibition (Allen et al, 2002;Muenster et al, 2008). Furthermore, the net secretion of ciprofloxacin was completely abolished by the specific BCRP inhibitor Ko143, in contrast with the partial inhibition evident with CsA and DIDS, P-gp/BCRP, and anion exchange inhibitors, respectively.…”

Section: Discussionsupporting

confidence: 87%

Intestinal Ciprofloxacin Efflux: The Role of Breast Cancer Resistance Protein (ABCG2)

Haslam¹,

Wright²,

O’Reilly³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Intestinal secretory movement of the fluoroquinolone antibiotic, ciprofloxacin, may limit its oral bioavailability. Active ATP-binding cassette ( , and verapamil as ABC-selective inhibitors. In addition, the regional variation in secretory capacity was investigated using male Han Wistar rat intestine mounted in Ussing chambers, and the first indicative measurements of ciprofloxacin transport by ex vivo human jejunum were made. Active, Ko143-sensitive ciprofloxacin secretion was observed in bcrp1-MDCKII cell layers, but in low-passage (BCRP-expressing) Caco-2 cell layers only a 54% fraction was Ko143-sensitive. Ciprofloxacin accumulation was lower in MRP4-HEK293 cells than in the parent line, indicating that ciprofloxacin is also a substrate for this transporter. Ciprofloxacin secretion by Caco-2 cell layers was not inhibited by MK571. Secretory flux showed marked regional variability in the rat intestine, increasing from the duodenum to peak in the ileum. Ciprofloxacin secretion was present in human jejunum and was reduced by Ko143 but showed marked interindividual variability. Ciprofloxacin is a substrate for human and rodent BCRP. An additional pathway for ciprofloxacin secretion exists in Caco-2 cells, which is unlikely to be MRP(4)-mediated. BCRP is likely to be the dominant transport mechanism for ciprofloxacin efflux in both rat and human jejunum.

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Section: Discussionsupporting

confidence: 87%

Intestinal Ciprofloxacin Efflux: The Role of Breast Cancer Resistance Protein (ABCG2)

Haslam¹,

Wright²,

O’Reilly³

et al. 2011

Drug Metab Dispos

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“…Likewise, polarized transcellular assays are not suitable for low permeable compounds, since they do not sufficiently penetrate the cells and therefore do not reach the export protein, potentially resulting in false-negative results. The existence of multiple binding sites on transport proteins could also add to the complexity of identifying substrate and inhibitor molecules in in vitro assay systems, leading to incorrect interpretation (Muenster et al, 2008;Giri et al, 2009). Careful selection of substrates and inhibitors is therefore critical for designing definitive studies, and may circumvent the current issues with very high experimental interlaboratory variability in in vitro assays .…”

Section: Lowmentioning

confidence: 99%

The Need for Human Breast Cancer Resistance Protein Substrate and Inhibition Evaluation in Drug Discovery and Development: Why, When, and How?

et al. 2014

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Although the multiplicity in transport proteins assessed during drug development is continuously increasing, the clinical relevance of the breast cancer resistance protein (BCRP) is still under debate. Here, our aim is to rationalize the need to consider BCRP substrate and inhibitor interactions and to define optimum selection and acceptance criteria between cell-based and vesicle-based assays in vitro. Information on the preclinical and clinical pharmacokinetics (PK), drug-drug interactions, and pharmacogenomics data was collated for 13 marketed drugs whose PK is reportedly associated with BCRP interaction. Clinical examples where BCRP impacts drug PK and efficacy appear to be rare and confounded by interactions with other transporters. Thirty-seven compounds were selected to be tested as BCRP substrates in a cell-based assay using MDCKII cells (Madin-Darby canine kidney cells) and 18 in membrane vesicles. Depending on the physicochemical compound properties, we observed both in vitro systems to give false-negative readouts. In addition, the inhibition potential of 19 compounds against BCRP was assessed in vesicles and in MDCKII cells, where we observed significant system and substrate-dependent IC 50 values. Therefore, neither of the two test systems is superior to the other. Instead, one system may offer advantages under certain situations (e.g., low permeability) and thus should be selected based on the physicochemical compound properties. Finally, given the clinical relevance of BCRP, we propose that its evaluation should remain issue-driven: for low permeable, low bioavailable drugs, in particular when other more common processes do not allow a mechanistic understanding of any unexpected absorption or brain disposition, and for drugs with a low therapeutic window.

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“…Examples are a wide range of anticancer drugs, sulfate and glucuronide conjugates of xenobiotics, tyrosine kinase inhibitors (TKIs), statins, fluorescent dyes and flavonoids [10,63] . In vitro assays showed that ABCG2 might have more than two binding sites, since ABCG2 inhibitors displayed different inhibition profiles, depending on the tested substrate [71][72][73] . For instance, the inhibitor Ko143 inhibited the transport of all the substrates tested by Giri et al [72] , which suggested its binding to a region that allosterically inhibits the transport of these substrates.…”

Section: Breast Cancer Resistance Proteinmentioning

confidence: 99%

“…However, the ABCG2 inhibitors elacridar, nelfinavir and Pluronic P85 seemed to bind to a different region, which inhibited the transport of the nucleoside analogs abacavir and zidovudine, but showed no or a partial effect on the transport of prazosin and imatinib. Muenster et al [73] showed that two different substrates, such as topotecan and albendazole sulfoxide, could simultaneously be transported without hindering each other's transport, which also suggest multiple binding sites in ABCG2. Furthermore, using homology modeling a complete homodimer ABCG2 model was created based on the crystal structure of the bacterial multidrug exporter Sav1866, which also suggested a multiple binding site [74] .…”

Section: Breast Cancer Resistance Proteinmentioning

confidence: 99%

How to overcome ATP-binding cassette drug efflux transporter-mediated drug resistance?

Jaramillo¹,

Saig²,

Cloos³

et al. 2018

CDR

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P-glycoprotein (ABCB1), multidrug resistance protein-1 (ABCC1) and breast cancer resistance protein (ABCG2) belong to the ATP-binding cassette (ABC) superfamily of proteins that play an important physiological role in protection of the body from toxic xenobiotics and endogenous metabolites. Beyond this, these transporters determine the toxicity profile of many drugs, and confer multidrug resistance (MDR) in cancer cells associated with a poor treatment outcome of cancer patients.It has long been hypothesized that inhibition of ABC drug efflux transporters will increase drug accumulation and thereby overcome MDR, but until now no approved inhibitor of these transporters is available in the clinic. In this review we present molecular strategies to overcome this type of drug resistance and discuss for each of these strategies their promising value or indicate underlying reasons for their limited success.

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Characterization of Substrates and Inhibitors for the In Vitro Assessment of Bcrp Mediated Drug–Drug Interactions

Abstract: Data suggest different modes of substrate and inhibitor binding to Bcrp. In order to not overlook potential drug-drug interactions when testing drug candidates for inhibitory potential towards Bcrp, distinct Bcrp probe substrates should be used.

Cited by 71 publications

References 30 publications

Intestinal Ciprofloxacin Efflux: The Role of Breast Cancer Resistance Protein (ABCG2)

Intestinal Ciprofloxacin Efflux: The Role of Breast Cancer Resistance Protein (ABCG2)

The Need for Human Breast Cancer Resistance Protein Substrate and Inhibition Evaluation in Drug Discovery and Development: Why, When, and How?

How to overcome ATP-binding cassette drug efflux transporter-mediated drug resistance?

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