Antidiabetic II Drug Metformin in Plants: Uptake and Translocation to Edible Parts of Cereals, Oily Seeds, Beans, Tomato, Squash, Carrots, and Potatoes Trine Eggen* ,† and Cathrine Lillo § † Bioforsk, Norwegian Institute for Agricultural and Environmental Research, Postveien 213, N-4353 Klepp St., Norway § Faculty of Science and Technology, Centre for Organelle Research, University of Stavanger, N-4036 Stavanger, Norway ABSTRACT: Residues of pharmaceuticals present in wastewater and sewage sludge are of concern due to their transfer to aquatic and terrestrial food chains and possible adverse effects on nontargeted organisms. In the present work, uptake and translocation of metformin, an antidiabetic II medicine, by edible plant species cultivated in agricultural soil have been investigated in greenhouse experiment. Metformin demonstrated a high uptake and translocation to oily seeds of rape (Brassica napus cv. Sheik and Brassica rapa cv. Valo); expressed as an average bioconcentration factor (BCF, plant concentration over initial concentration in soil, both in dry weight), BCF values as high as 21.72 were measured. In comparison, BCFs for grains of the cereals wheat, barley, and oat were in the range of 0.29-1.35. Uptake and translocation to fruits and vegetables of tomato (BCFs 0.02-0.06), squash (BCFs 0.12-0.18), and bean (BCF 0.88) were also low compared to rape. BCFs for carrot, potato, and leaf forage B. napus cv. Sola were similar (BCF 1-4). Guanylurea, a known degradation product of metformin by microorganisms in activated sludge, was found in barley grains, bean pods, potato peel, and small potatoes. The mechanisms for transport of metformin and guanidine in plants are still unknown, whereas organic cation transporters (OCTs) in mammals are known to actively transport such compounds and may guide the way for further understanding of mechanisms also in plants. KEYWORDS: bioconcentration factor (BCF), Brassica, metformin, OCTs, pharmaceuticals, seeds ■ INTRODUCTION Pharmaceuticals became recognized as emerging environmental contaminants at the end of the 1990s. 1-3 Pathways for the entrance of pharmaceuticals to the environment, and subsequently to the human food web, are application of manure (veterinary pharmaceuticals), 4,5 use of sewage sludge as soil fertilizer and conditioner, 6-8 and irrigation of fields with wastewater containing pharmaceutical residues. 8,9 The concerns about residues of pharmaceuticals in the environment are related to these compounds’ high biological activity and unknown effects on nontargeted organisms and healthy individuals. Many high production volume medicines are poorly investigated with regard to their environmental distribution and transport. The antidiabetic II medicine metformin is among the most prescribed pharmaceuticals, 10,11 and is excreted nonmetabolized in the urine. 12 Thus, not surprisingly, metformin has been detected in surface water, in concen- trations up to 1.7 μgL -1 , 13,14 in wastewater treatment plant influent and effluent in the ranges of 101-129 and 2.2-21 μg L -1 , respectively, 14 and in sewage sludge in the range of 500- 1600 μg kg -1 dw. 15 The environmental fate of metformin is not clear, but, apparently, metformin is degraded by bacteria in activated sludge to the dead-end product guanylurea under aerobic conditions. 16 Guanylurea has also been suggested as a degradation product of metformin during wastewater treat- ment. 14 Recently, we demonstrated that metformin is taken up in agricultural plants and translocated to seeds. 17 Although the fate of metformin in plants is not known, it is possible that the plant attempts to accumulate and, if feasible, metabolize metformin as related nitrogen-containing natural compounds, for example, galegine and arginine (Figure 1). French lilac or goat’s rue (Galega officinalis) has been used as an herbal remedy against several illnesses, including diabetes symptoms, since medieval times. G. officinalis is rich in guanidine and galegine (isoamylene guanidine or dimethylallylguanidine), both of which were studied and used as antidiabetic agents in the beginning of the previous century. 18 Several biguanides were later tested for their effects in humans or other mammals, and metformin arose as a suitable compound without side effects during the 1970s. 18 Today, generic knowledge on pharmaceutical compounds in the environment, their chemical and physical properties, and uptake and translocation in plants is insufficient. Due to the high environmental loading of pharmaceuticals and general lack of information on the environmental fate of this group of bioactive compounds, increased knowledge is necessary to allow regulative environmental and food authorities to take action, for example, introduce recommendations or restrictions concerning the growth of certain crops in fields with elevated concentrations of such contaminants. The goals of the present study were to (i) determine the uptake and translocation of metformin into different edible plant compartments used as forage or human food and (ii) Received: March 26, 2012 Revised: June 17, 2012 Accepted: June 19, 2012 Published: June 19, 2012 Article pubs.acs.org/JAFC © 2012 American Chemical Society 6929 dx.doi.org/10.1021/jf301267c | J. Agric. Food Chem. 2012, 60, 6929-6935