Interactions of Cyclosporin A with Breast Cancer Resistance Protein

Xia, Cindy Q.; Liu, Ning; Miwa, Gerald T.; Gan, Lawrence L.

doi:10.1124/dmd.106.011866

Cited by 66 publications

(47 citation statements)

References 39 publications

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“…The cells were incubated at 37jC, and 50-AL aliquots were taken from each compartment at 1, 2, 3, and 4 h. The appearance of radioactivity in the opposite compartment was measured and presented as the fraction of total radioactivity added at the beginning of the experiment. Calculations were done as described in detail elsewhere (23). In brief, the cumulative amount of imatinib (Q) on the receiver side was initially plotted as a function of time.…”

Section: Methodsmentioning

confidence: 99%

Interaction of Imatinib with Human Organic Ion Carriers

Franke

Filipski

et al. 2008

Clinical Cancer Research

208

176

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Purpose: The activity of imatinib in leukemia has recently been linked with expression of the organic cation transporter 1 (OCT1) gene SLC22A1. Here, we characterized the contribution of solute carriers to imatinib transport in an effort to further understand mechanisms involved in the intracellular uptake and retention (IUR) of the drug. Experimental Design: IUR of [ 3 H]imatinib was studied in Xenopus laevis oocytes and HEK293 cells expressing OATP1A2, OATP1B1, OATP1B3, OCT1-3, OCTN1-2, or OAT1-3. Gene expression was determined in nine leukemia cell lines using the Affymetrix U133 array. Results: Imatinib was not found to be a substrate for OCT1 in oocytes (P = 0.21), whereas in HEK293 cells IUR was increased by only 1.20-fold relative to control cells (P = 0.002). Furthermore, in 74 cancer patients, the oral clearance of imatinib was not significantly altered in individuals carrying reduced-function variants in SLC22A1 (P = 0.99). Microarray analysis indicated that SLC22A1 was interrelated with gene expression of various transporters, including ABCB1, ABCC4, ABCG2 (negative), and OATP1A2 (positive). Imatinib was confirmed to be a substrate for the three efflux transporters (P < 0.05) as well as for OATP1A2 (P = 0.0001).Conclusions:This study suggests that SLC22A1 expression is a composite surrogate for expression of various transporters relevant to imatinib IUR. This observation provides a mechanistic explanation for previous studies that have linked SLC22A1 with the antitumor activity of imatinib. Because of its high expression in the intestine, ciliary body, gliomas, and leukemia cells, OATP1A2 may play a key role in imatinib pharmacokinetics-pharmacodynamics.

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Section: Methodsmentioning

confidence: 99%

Interaction of Imatinib with Human Organic Ion Carriers

Franke

Filipski

et al. 2008

Clinical Cancer Research

208

176

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“…Furthermore, concurrent intake with quinine (an inhibitor of P-gp and OCT) resulted in a significant reduction in biliary excretion of unbound berberine (Tsai and Tsai, 2004), suggesting that the efflux transporters expressed in the liver may play an important role in biliary excretion of berberine. However, intravenous coadministration with cyclosporine, an inhibitor of P-gp (Cummins et al, 2004), organic anion-transporting polypeptide (Shitara et al, 2009), breast cancer resistance protein (Xia et al, 2007), and CYP3A (Cummins et al, 2004) led to a dramatic decrease in unbound concentrations of berberine in the liver and bile but not in blood (Tsai and Tsai, 2004). Therefore, the role drug transporters may play in the entire first-pass elimination of berberine would be more complex than we assumed, and a knockout mouse model of each transporter (in particular P-gp) will be required to clarify this issue if no highly specific chemical inhibitor of each of the drug transporters is available.…”

Section: First-pass Elimination and Tissue Distribution Of Berberinementioning

confidence: 99%

Extensive Intestinal First-Pass Elimination and Predominant Hepatic Distribution of Berberine Explain Its Low Plasma Levels in Rats

Liu¹,

Hao²,

Xie³

et al. 2010

Drug Metab Dispos

283

235

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ABSTRACT:Berberine, one of the most commonly used natural products, exhibits a poor plasma concentration-effect relationship whose underlying mechanisms remain largely unclear. This study was designed to test the hypothesis that extensive first-pass elimination and abundant tissue distribution of berberine may be its specific pharmacokinetic properties. For that, four different dosing routes, intragastric, intraduodenal, intraportal, and intravenous, were used to investigate the gastric, intestinal, and hepatic first-pass elimination of berberine. After intragastric dosing, approximately half of berberine ran intact through the gastrointestinal tract and another half was disposed of by the small intestine, leading to an extremely low extent of absolute oral bioavailability in rats (0.36%). Moreover, the major berberine metabolites were identified and quantified in rat enterocyte S9 fractions, portal vein plasma, and intestinal perfusates; plasma concentrations and tissue distribution of berberine and its major metabolites were determined as well. Data indicated that M1, M2 glucuronide, and M3 were the major metabolites generated from the small intestine and that there was a 70-fold increase in the ratio of the area under the concentration-time curve value for berberine (liver versus plasma). We conclude that intestinal first-pass elimination of berberine is the major barrier of its oral bioavailability and that its high extraction and distribution in the liver could be other important factors that lead to its low plasma levels in rats.

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“…Thirty-seven compounds were selected to be tested as BCRP substrates in M-BCRP cells. Six compounds were selected as negative controls: CsA and ritonavir, previously reported as non-BCRP substrates (Gupta et al, 2004;Xia et al, 2007); propranolol, metoprolol, and verapamil, highly permeable drugs with no records as BCRP substrates; and metformin, a low permeability drug with questionable BCRP substrate data (Hemauer et al, 2010). Propranolol, metoprolol, and verapamil showed ER in M-BCRP cells of around 1, which was insensitive to Ko143 and equivalent in MDCKII (parental cells); the same was observed for fumitremorgin C (FTC) ( Table 2).…”

Section: Bcrp Substrate In Vitro Assaymentioning

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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Interactions of Cyclosporin A with Breast Cancer Resistance Protein

Cited by 66 publications

References 39 publications

Interaction of Imatinib with Human Organic Ion Carriers

Interaction of Imatinib with Human Organic Ion Carriers

Extensive Intestinal First-Pass Elimination and Predominant Hepatic Distribution of Berberine Explain Its Low Plasma Levels in Rats

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

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