Nitrofurantoin is a commonly used urinary tract antibiotic prescribed to lactating woman. It is actively transported into human and rat milk by an unknown mechanism. Our group has demonstrated an important role of the breast cancer resistance protein (BCRP/ABCG2) in the secretion of xenotoxins into the milk. This ATP-binding cassette drug efflux transporter extrudes xenotoxins from cells in intestine, liver, mammary gland, and other organs, affecting the pharmacological and toxicological behavior of many compounds. We investigated whether Bcrp1 is involved in the pharmacokinetic profile of nitrofurantoin and its active secretion into the milk. Using polarized cell lines, we found that nitrofurantoin is efficiently transported by murine Bcrp1 and human BCRP. After oral administration of 10 mg/kg nitrofurantoin, the area under the plasma concentrationtime curve in Bcrp1 knockout mice was almost 4-fold higher than in wild-type mice (148.8 +/- 30.4 versus 37.5 +/- 6.8 min x microg/ml); and after i.v. administration (5 mg/kg), 2-fold higher (139.2 +/- 22.0 versus 73.9 +/- 9.0 min x microg/ml). Hepatobiliary excretion of nitrofurantoin was almost abolished in Bcrp1 knockout mice (9.6 +/- 3.2 versus 0.2 +/- 0.1% in wild-type and Bcrp1 knockout mice, respectively). The milk-to-plasma ratio of nitrofurantoin was almost 80 times higher in wild-type compared with Bcrp1 knockout lactating female mice (45.7 +/- 16.2 versus 0.6 +/- 0.1). Nitrofurantoin elimination via milk was quantitatively even higher than hepatobiliary elimination. We conclude that Bcrp1 is an important determinant for the bioavailability of nitrofurantoin and the main mechanism involved in its hepatobiliary excretion and secretion into the milk.

The breast cancer resistance protein (BCRP/ABCG2) affects pharmacokinetics, hepatobiliary excretion, and milk secretion of the antibiotic nitrofurantoin.

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 10 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 10 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 33 to 80 and 19 to 43 ng/kg bw 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 20 × 105 or greater for carcinogenicity and at 25 × 103 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 10 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 104 calculated for non-neoplastic effects do not indicate a health concern

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Scientific Opinion on nitrofurans and their metabolites in food

Breast cancer resistance protein (BCRP/ABCG2) is an ATP-binding cassette efflux transporter, important in drug disposition and in the development of multidrug resistance in cancer. Flavonoids, a large class of natural compounds widely present in the diet and herbal products, have been shown in vitro to be BCRP inhibitors. The flavonoid chrysin is a potent inhibitor of BCRP, inhibiting the efflux of mitoxantrone with an IC(50) of 0.39 microM in BCRP-overexpressing human MCF-7 breast cancer cells. The purpose of this study was to investigate the potential pharmacokinetic interactions between chrysin and nitrofurantoin (a specific BCRP substrate) in rats. In Madin-Darby canine kidney cells expressing human BCRP or murine Bcrp1, the polarized transport of nitrofurantoin was effectively inhibited by chrysin at concentrations of 20 and 100 microM. Compared with the vehicle-treated group, p.o. coadministration of chrysin (200 mg/kg) significantly increased the area under the curve (AUC) and C(max) of nitrofurantoin (10 mg/kg) by 1.76- (p < 0.01) and 1.72-fold (p < 0.05), respectively. When nitrofurantoin (2 mg/kg) was given i.v., administration of chrysin (50 mg/kg i.p.) significantly increased the AUC of nitrofurantoin (123 +/- 34.0 versus 91.5 +/- 18.0 microg/ml x min in controls, p < 0.05). Moreover, the cumulative hepatobiliary excretion of nitrofurantoin (1.5 mg/kg i.v.) was significantly decreased by approximately 75% at the end of 120 min after the coadministration of chrysin (50 mg/kg i.p.). Taken together, these results indicate that the flavonoid chrysin significantly inhibits nitrofurantoin transport mediated by human BCRP and murine Bcrp1. Bcrp1 inhibition by chrysin is likely one potential mechanism for the observed chrysin-nitrofurantoin pharmacokinetic interactions in rats.

https://dmd.aspetjournals.org/content/dmd/early/2006/11/08/dmd.106.011684.full.pdf

Effects of the Flavonoid Chrysin on Nitrofurantoin Pharmacokinetics in Rats: Potential Involvement of ABCG2

Various nitrofuran derivatives have been tested with Chinese hamster cells growing in vitro to determine their toxicity and radiosensitizing effectiveness. All nitrofurans tested displayed a greater radiosensitizing potential than p-nitroacetophenone for hypoxic cells at concentrations producing no acute toxicity. The most effective compound tested to date is nifuraldezone which at 250 μm in complete medium gives the same extent of radiosensitization (ER∼2·85) as oxygen in air-saturated medium. Additional nitroheterocyclic compounds in current clinical usage have also been characterized. The chemical and pharmacological properties of the various compounds are discussed in relation to their application in animal tumour studies. High water solubility appears to be an important property for radiosensitizers to be used in animal tumour studies. A positive demonstration of radiosensitization in vivo with nitroheterocyclic drugs will depend upon whether or not a sensitizing concentration of the drugs c...

C. M. Harrington

Papers

Studies on the distribution and excretion of certain nitrofurans.