In Vivo Inhibition of BCRP/ABCG2 Mediated Transport of Nitrofurantoin by the Isoflavones Genistein and Daidzein: A Comparative Study in Bcrp1 −/− Mice

Merino, Gracia; Pérez, Marcela Mastachi; Real, Rebeca; Egido, Estefanía; Prieto, J. E.; Alvarez, Ana I.

doi:10.1007/s11095-010-0208-5

Cited by 29 publications

(24 citation statements)

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“…To further demonstrate an in vivo Abcg2/ ABCG2 inhibitory role of TCBZ metabolites in other relevant drug-drug interactions and biological processes, the effect of the coadministration of TCBZSO on the secretion into milk of the antibacterial nitrofurantoin, an in vivo Abcg2/ABCG2 model substrate, was studied. Nitrofurantoin transfer into milk has been previously used as an experimental setting to test the in vivo effect of ABCG2 inhibitors (21,33).…”

Section: Resultsmentioning

confidence: 99%

“…Several studies have managed to increase the bioavailability and milk secretion of antibacterial agents, such as nitrofurantoin, or antitumorals, such as topotecan, or to improve brain penetration of the antitumoral imatinib with the use of ABCG2 and Pglycoprotein inhibitors, such as elacridar, the benzimidazole pantoprazole, or isoflavones (2,11,14,21,25). However, it has to be noted that the use of TCBZ for this purpose may be controversial in animals whose products are destined for human consumption or in areas of parasite endemicity due to the potential development of resistance.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the overexpression of ABC transporters has been associated with multidrug resistance (MDR), a major impediment to successful cancer chemotherapy. Increasing interest has been given to the development of inhibitors to overcome MDR and to increase oral bioavailability and tissue penetration or to decrease milk secretion of its substrates (21,28).…”

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confidence: 99%

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The Anthelmintic Triclabendazole and Its Metabolites Inhibit the Membrane Transporter ABCG2/BCRP

Barrera

Otero

Egido

et al. 2012

Antimicrob Agents Chemother

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dABCG2/BCRP is an ATP-binding cassette transporter that extrudes compounds from cells in the intestine, liver, kidney, and other organs, such as the mammary gland, affecting pharmacokinetics and milk secretion of antibiotics, anticancer drugs, and other compounds and mediating drug-drug interactions. In addition, ABCG2 expression in cancer cells may directly cause resistance by active efflux of anticancer drugs. The development of ABCG2 modulators is critical in order to improve drug pharmacokinetic properties, reduce milk secretion of xenotoxins, and/or increase the effective intracellular concentrations of substrates. Our purpose was to determine whether the anthelmintic triclabendazole (TCBZ) and its main plasma metabolites triclabendazole sulfoxide (TCBZSO) and triclabendazole sulfone (TCBZSO 2 ) inhibit ABCG2 activity. ATPase assays using human ABCG2-enriched membranes demonstrated a clear ABCG2 inhibition exerted by these compounds. Mitoxantrone accumulation assays using murine Abcg2-and human ABCG2-transduced MDCK-II cells confirmed that TCBZSO and TCBZSO 2 are ABCG2 inhibitors, reaching inhibitory potencies between 40 and 55% for a concentration range from 5 to 25 M. Transepithelial transport assays of ABCG2 substrates in the presence of both TCBZ metabolites at 15 M showed very efficient inhibition of the Abcg2/ ABCG2-mediated transport of the antibacterial agents nitrofurantoin and danofloxacin. TCBZSO administration also inhibited nitrofurantoin Abcg2-mediated secretion into milk by more than 2-fold and increased plasma levels of the sulfonamide sulfasalazine by more than 1.5-fold in mice. These results support the potential role of TCBZSO and TCBZSO 2 as ABCG2 inhibitors to participate in drug interactions and modulate ABCG2-mediated pharmacokinetic processes.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The Anthelmintic Triclabendazole and Its Metabolites Inhibit the Membrane Transporter ABCG2/BCRP

Barrera

Otero

Egido

et al. 2012

Antimicrob Agents Chemother

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“…In another in vitro study, the one-electron reduction of nitrofurantoin by rat liver mitochondria with the generation of the nitroanion radical and the superoxide anion could be demonstrated by direct electron spin resonance spectroscopy and spin trapping experiments, respectively (Moreno et al, 1984). An increasing body of literature (Oo et al, 2001;Merino et al, 2005Merino et al, , 2010Wang and Morris, 2007;Wang et al, 2008) indicates that, based on both in vitro and in vivo studies using knock-out mice, nitrofurantoin is a substrate of the transmembrane breast cancer resistance protein (BCRP/ABCG2), a member of the ATP-binding cassette family of transporters affecting the kinetics of several drugs, toxins and food/feed components. Remarkable differences in oral bioavailability (almost a 2-fold increase), hepatobiliary excretion rate (nearly abolished) and milk-plasma ratio (80-fold decrease) were reported between BCRP-/-and wild-type nitrofurantoin-treated mice (Merino et al, 2005).…”

Section: Laboratory Animalsmentioning

confidence: 99%

“…Remarkable differences in oral bioavailability (almost a 2-fold increase), hepatobiliary excretion rate (nearly abolished) and milk-plasma ratio (80-fold decrease) were reported between BCRP-/-and wild-type nitrofurantoin-treated mice (Merino et al, 2005). The effects of the co-administration of nitrofurantoin and a mixture of two soy isoflavones known for their inhibitory effects on drug transporters (Okura et al, 2010), namely genistein and daidzein, were investigated in mice (Merino et al, 2010). Wild-type mice were orally dosed with nitrofurantoin alone (20 mg/kg b.w.)…”

Section: Laboratory Animalsmentioning

confidence: 99%

Scientific Opinion on nitrofurans and their metabolites in food

Panel¹

2015

EFS2

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Nitrofurans are antimicrobial agents not authorised for use in food-producing animals in the European Union. Nitrofurans are rapidly metabolised, occurring in animal tissues as protein-bound metabolites. The European Commission requested EFSA to provide a scientific opinion on the risks to human health related to the presence of nitrofurans in food and whether a reference point for action (RPA) of 1.0 µg/kg for the marker metabolites is adequate to protect public health. Data on occurrence of nitrofuran marker metabolites in food were extracted from the national residue monitoring plan results and from the Rapid Alert System for Food and Feed (RASFF). The CONTAM Panel concluded that these data were too limited to carry out a reliable human dietary exposure assessment. Instead, human dietary exposure was calculated for a scenario in which a single nitrofuran marker metabolite is present at 1.0 µg/kg in foods of animal origin, excluding milk and dairy products. The mean chronic dietary exposure for this worst-case scenario would range from 3.3 to 8.0 and 1.9 to 4.3 ng/kg b.w. per day for toddlers and adults, respectively. Nitrofurans and their marker metabolites, generally, are genotoxic and carcinogenic and, also, have non-neoplastic effects in animals. Margins of exposure (MOEs) were calculated at 2.0 × 10 5 or greater for carcinogenicity and at 2.5 × 10 3 or greater for non-neoplastic effects. The CONTAM Panel concluded that it is unlikely that exposure to food contaminated with nitrofuran marker metabolites at or below 1.0 µg/kg is a health concern. A scenario in which foods are considered to be contaminated with semicarbazide, from use of carrageenan as a food additive, at 1 µg/kg was used to assess whether it is appropriate to apply the RPA to foods of non-animal origin; MOEs of greater than 10 4 calculated for nonneoplastic effects do not indicate a health concern.© European Food Safety Authority, 2015 However, the opinion also identified certain categories of non-allowed pharmacologically active substances that are considered to be outside the scope of the procedure, including substances that are high potency carcinogens, such as nitrofurans. As nitrofurans are excluded from that opinion, and taking into account that the presence of SEM in food may be from sources other than use of nitrofurazone, the European Commission (EC) requested the European Food Safety Authority (EFSA) for a scientific opinion on the risks to human health related to the presence of nitrofurans and their metabolites in food. The opinion should include (a) an evaluation of the toxicity of nitrofurans and their metabolites for humans, considering all relevant toxicological endpoints and identification of the toxicological relevance of nitrofurans and their metabolites present in food, and (b) an exposure assessment of the EU population to nitrofurans and their metabolites from food, including the consumption patterns of specific (vulnerable) groups of the population. In addition, the opinion should assess the appropriateness of...

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Flavonoids and Drug Interactions

Yáñez

Chemuturi

Womble

et al. 2012

Flavonoid Pharmacokinetics

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In Vivo Inhibition of BCRP/ABCG2 Mediated Transport of Nitrofurantoin by the Isoflavones Genistein and Daidzein: A Comparative Study in Bcrp1 −/− Mice

Abstract: Our data showed that in vivo interaction of high doses of soy isoflavones with BCRP substrates may affect plasma levels but the main effect occurs in specific target organs, in our case, liver and mammary glands.

Cited by 29 publications

References 43 publications

The Anthelmintic Triclabendazole and Its Metabolites Inhibit the Membrane Transporter ABCG2/BCRP

The Anthelmintic Triclabendazole and Its Metabolites Inhibit the Membrane Transporter ABCG2/BCRP

Scientific Opinion on nitrofurans and their metabolites in food

Flavonoids and Drug Interactions

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