Inhibitory Effects of Terpenoids on Multidrug Resistance-Associated Protein 2- and Breast Cancer Resistance Protein-Mediated Transport

Yoshida, Naoko; Takada, Tappei; Yamamura, Yoshikazu; Adachi, Isao; Suzuki, Hiroshi; Kawakami, Junichi

doi:10.1124/dmd.107.019513

Cited by 62 publications

(34 citation statements)

References 22 publications

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“…E 2 17βG is a well known substrate for the study of MRPs (such as MRP1, MRP2, MRP3, MRP4 and MRP7); in recent years, studies had shown that it could be transported by Pgp, BCRP and OATP as well. Regardless, E 2 17βG has a significantly higher affinity toward MRP1 and MRP2 compared to other transporters (38)(39)(40)(41). Despite the high affinity of E 2 17βG with MRP1, there is a considerably lower expression level of MRP1 compared to MRP2 in Caco-2 cells.…”

Section: Discussionmentioning

confidence: 77%

Effects of Monoglycerides on Rhodamine 123 Accumulation, Estradiol 17 β-D-Glucuronide Bidirectional Transport and MRP2 Protein Expression within Caco-2 cells

Jia

2008

J Pharm Pharm Sci

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-Purpose. Oral drug development had been hindered by the bioavailability issue despite vast market popularity. Lipid excipients had shown to enhance bioavailability of a number of reformulated hydrophobic oral drugs, yet the underlying mechanisms of action by lipids are still unclear. One proposed mechanism is that lipid excipients could facilitate drug uptake by altering the activities of apical membrane intestinal efflux transporters. Thus, this study aimed to investigate the effects of 1-monopalmitin, 1-monoolein and 1-monostearin on the efflux activity and protein expression of multidrug resistance-associated protein 2 (MRP2) in vitro. Methods. The 24-hour non-cytotoxic ranges of these monoglycerides were first determined using MTS and LDH assays in Caco-2 cells. Then, both accumulation and bidirectional transport studies were conducted using 10 μM rhodamine 123 (Rh123) and 10 nM estradiol 17 β-D-glucuronide (E 2 17βG), respectively, to assess the functional activities of MRP2. 50 µM MK-571, a specific MRP1 and MRP2 inhibitor, was used as the positive control in both studies. Western blotting was followed to determine the effect of these monoglycerides on MRP2 protein expression. Results. Caco-2 cells were viable when treated with 1-monopalmitin, 1-monostearin and 1-monoolein at concentrations equal or less than 1000 µM, 1000 µM and 500 µM, respectively. Cells treated with 1-monoplamitin, 1-monostearin, 1-monoolein and MK571 resulted in significant increases in Rh123 accumulation and decreases in E 2 17βG efflux ratio compared to the control (medium treated only). MRP2 protein expressions in 1-monopalmitin and 1-monoolein treated cells were decreased by 19% and 35% compared to the control; however, there was no change of MRP2 protein expression in 1-monostearin treated cells. Conclusions. These findings suggested that 1-monoolein, 1-monostearin and 1-monopalmitin could attenuate the activity of MRP2 and possibly other efflux transporters in Caco-2 cells. The reduction of efflux activity of MRP2 by 1-monoolein treatment could be partially accounted by the non-specific down-regulation of MRP2 protein expression.

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Section: Discussionmentioning

confidence: 77%

Effects of Monoglycerides on Rhodamine 123 Accumulation, Estradiol 17 β-D-Glucuronide Bidirectional Transport and MRP2 Protein Expression within Caco-2 cells

Jia

2008

J Pharm Pharm Sci

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“…The transporter spectrum of some saponins may overlap with those of statins. For example, ginsenoside Rh 2 isolated from ginsenoside is a substrate of BCRP (Jin et al, 2006), and glycyrrhetic acid derived from licorice is a moderate inhibitor of MRP2 and BCRP (Yoshida et al, 2008). Although this overlap may lead to potential DDI issues, no studies or clinical reports examining these issues have been published.…”

Section: Discussionmentioning

confidence: 94%

The Hepatobiliary Disposition of Timosaponin B2 Is Highly Dependent on Influx/Efflux Transporters but Not Metabolism

Sheng

Tian

et al. 2014

Drug Metab Dispos

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The purpose of this study was to characterize the hepatobiliary disposition of timosaponin B2 (TB-2), a natural saponin. Although TB-2 has multiple pharmacologic activities, the mechanism of its hepatobiliary disposition has not been explored. Because the metabolism of TB-2 is limited and the accumulation of TB-2 in primary hepatocytes is highly temperature dependent (93% of its accumulation is due to active uptake), the contribution of hepatic transporters was investigated. Organic anion-transporting polypeptide (OATP) 1B1-and OATP1B3-transfected human embryonic kidney 293 cells were employed. TB-2 serves as a substrate for OATP1B1 and OATP1B3, with the former playing a predominant role in the hepatic uptake of TB-2. An inhibition study in sandwich-cultured rat hepatocytes suggested that TB-2 is a substrate for both breast cancer resistance protein (Bcrp) and multidrug resistance-associated protein 2 (Mrp2), consistent with its high biliary excretion index (43.1-44.9%). This hypothesis was further verified in BCRP and MRP2 membrane vesicles. The cooperation of uptake and efflux transporters in TB-2 hepatic disposition could partially explain the doublepeak phenomenon observed in rat plasma and liver and biliary clearance, which accounted for 70% of the total TB-2 clearance. Moreover, TB-2 significantly increased the rosuvastatin concentration in rat plasma in a concentration-dependent manner and decreased its biliary excretion, which corresponded to reductions in rosuvastatin accumulation in hepatocytes and the biliary excretion index in sandwich-cultured rat hepatocytes, representing a perfect example of a potential saponin-statin drug-drug interaction. These studies demonstrate that transporters (Oatp, Bcrp/Mrp2), but not metabolism, contribute significantly to rat TB-2 hepatobiliary disposition.

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“…Natural Products. Several diet-derived/natural product constituents, such as curcumin, daidzein, genistein, chrysin, 7,8-benzoflavone, and glycyrrhetic acid, have been shown to inhibit human BCRP in vitro (Zhang et al, 2005a;Yoshida et al, 2008;Merino et al, 2010;Tamaki et al, 2010). In addition, a mixture of the soy isoflavones genistein and daidzein was shown to inhibit Bcrp in wild-type but not Bcrp-knockout mice, supporting specificity for Bcrp inhibition (Merino et al, 2010).…”

Section: Orgmentioning

confidence: 99%

Breast Cancer Resistance Protein (ABCG2) in Clinical Pharmacokinetics and Drug Interactions: Practical Recommendations for Clinical Victim and Perpetrator Drug-Drug Interaction Study Design

et al. 2015

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Breast cancer resistance protein (BCRP; ABCG2) limits intestinal absorption of low-permeability substrate drugs and mediates biliary excretion of drugs and metabolites. Based on clinical evidence of BCRP-mediated drug-drug interactions (DDIs) and the c.421C>A functional polymorphism affecting drug efficacy and safety, both the US Food and Drug Administration and European Medicines Agency recommend preclinical evaluation and, when appropriate, clinical assessment of BCRP-mediated DDIs. Although many BCRP substrates and inhibitors have been identified in vitro, clinical translation has been confounded by overlap with other transporters and metabolic enzymes. Regulatory recommendations for BCRP-mediated clinical DDI studies are challenging, as consensus is lacking on the choice of the most robust and specific human BCRP substrates and inhibitors and optimal study design. This review proposes a path forward based on a comprehensive analysis of available data. Oral sulfasalazine (1000 mg, immediate-release tablet) is the best available clinical substrate for intestinal BCRP, oral rosuvastatin (20 mg) for both intestinal and hepatic BCRP, and intravenous rosuvastatin (4 mg) for hepatic BCRP. Oral curcumin (2000 mg) and lapatinib (250 mg) are the best available clinical BCRP inhibitors. To interrogate the worst-case clinical BCRP DDI scenario, study subjects harboring the BCRP c.421C/C reference genotype are recommended. In addition, if sulfasalazine is selected as the substrate, subjects having the rapid acetylator phenotype are recommended. In the case of rosuvastatin, subjects with the organic anion-transporting polypeptide 1B1 c.521T/T genotype are recommended, together with monitoring of rosuvastatin's cholesterol-lowering effect at baseline and DDI phase. A proof-of-concept clinical study is being planned by a collaborative consortium to evaluate the proposed BCRP DDI study design.

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Inhibitory Effects of Terpenoids on Multidrug Resistance-Associated Protein 2- and Breast Cancer Resistance Protein-Mediated Transport

Cited by 62 publications

References 22 publications

Effects of Monoglycerides on Rhodamine 123 Accumulation, Estradiol 17 β-D-Glucuronide Bidirectional Transport and MRP2 Protein Expression within Caco-2 cells

Effects of Monoglycerides on Rhodamine 123 Accumulation, Estradiol 17 β-D-Glucuronide Bidirectional Transport and MRP2 Protein Expression within Caco-2 cells

The Hepatobiliary Disposition of Timosaponin B2 Is Highly Dependent on Influx/Efflux Transporters but Not Metabolism

Breast Cancer Resistance Protein (ABCG2) in Clinical Pharmacokinetics and Drug Interactions: Practical Recommendations for Clinical Victim and Perpetrator Drug-Drug Interaction Study Design

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