Bioavailability of flumequine and diclofenac in mice exposed to a metal-drug chemical cocktail. Evaluation of the protective role of selenium.

BACKGROUND AND PURPOSE: Organisms, including humans, are subjected to the simultaneous action of a wide variety of pollutants, the effects of which should not be considered in isolation, as many synergies and antagonisms have been found between many of them. Therefore, this work proposes an in vivo study to evaluate the effect of certain metal contaminants on the bioavailability and metabolism of pharmacologically active compounds. Because the most frequent entry vector is through ingestion, the influence of the gut microbiota and the possible protective effects of selenium has been additionally evaluated. EXPERIMENTAL APPROACH: A controlled exposure experiment in mammals (Mus musculus) to a "chemical cocktail" consisting of metals and pharmaceuticals (diclofenac and flumequine). The presence of selenium has also been evaluated as an antagonist. Mouse plasma samples were measured by UPLC-QTOF. A targeted search of 48 metabolites was also performed. KEY RESULTS: Metals significantly affected the FMQ plasma levels when the gut microbiota was depleted. Hydroxy FMQ decreased if metals were present. Selenium minimized this decrease. The 3-hydroxy DCF metabolite was not found in any case. Changes in some metabolic pathways are discussed. CONCLUSIONS AND IMPLICATIONS: The presence of metals in the mouse diet as well as the prior treatment of mice with an antibiotic mixture (Abxs), which deplete the gut microbiota, has a decisive effect on the bioavailability and metabolism of the tested pharmaceuticals and dietary selenium minimize some of their effects.

Green Method for the Selective Electromembrane Extraction of Parabens and Fluoroquinolones in the Presence of NSAIDs by Using Biopolymeric Chitosan Films.

A chitosan biopolymeric membrane was successfully used as a support in a green electromembrane extraction procedure for the simultaneous and selective extraction of seven parabens and three fluoroquinolones in the presence of three non-steroidal anti-inflammatory drugs. The optimal experimental conditions (10 mL donor phase and 50 µL acceptor phase, pH 10 in both phases; 80 V of applied voltage during 15 min of extraction time) were determined, providing high enrichment factors for six of the studied parabens (EF ≥ 90) and the three fluoroquinolones (EF ≥ 50). Wide linear concentration ranges (0.5-500 µg L-1), good linearity (>97%), low limits of detection (0.2-1.1 µg L-1), and good repeatability (relative standard deviation values 4-10%) were achieved. The proposed method was successfully applied for the extraction of the target analytes from different kinds of water samples (river, lake, and swimming pool). The usage of a chitosan membrane in the extraction process presents many advantages, as it is a biodegradable and versatile support, offering a good alternative to commercial plastic materials commonly used in this methodology and these procedures.

Chitosan biofilms: Insights for the selective electromembrane extraction of fluoroquinolones from biological samples.

A selective electromembrane extraction procedure for the extraction of Enrofloxacin, Marbofloxacin and Flumequine, usually employed as antibiotic in veterinarian use, is proposed by using a chitosan biofilm, composed by 60% (w/w) chitosan and 40% (w/w) Aliquat®336, as active biopolymeric support. The interaction mechanism occurring between the target drugs and the biopolymer has been deeply studied using the Quantum Theory of Atoms in Molecules. The obtained results show the interaction between the extracted fluoroquinolones and the biomembrane is stabilized by two hydrogen bonds formed between both the carboxyl and keto groups of the drugs with both the amine and hydroxyl groups of glucosamine in the biopolymer. The energetic results agree with the high extraction efficiency obtained for Marbofloxacin, Enrofloxacin and Flumequine in terms of enrichment factors (83, 82 and 58, respectively) in presence of other fluoroquinolones. Under optimum conditions, the proposed electromembrane extraction method exhibits wide linear ranges of 4.2-200 µg L-1, 5.6-200 µg L-1 and 5.1-200 µg L-1, respectively; low limits of detection close to 1.3 µg L-1 and appropriate repeatability (relative standard deviation values 4-7%).

Monitoring of pharmaceuticals in aquatic biota (Procambarus clarkii) of the Doñana National Park (Spain).

In this work the presence of different pharmaceuticals at Doñana National Park (Spain) and their main entry sources (input source or entry points) have been stated over the 2011-2016 years period. Twenty-three selected pharmaceuticals (corresponding to eight therapeutic families) were evaluated in crayfish and water samples from Doñana National Park (Spain) (six sampling points selected in order to cover different possible pollution sources into and surrounding the Park). The multiresidue determination was carried out using enzymatic-microwave assisted extraction prior to high performance liquid chromatography mass spectrometry detection. Sulphonamides (sulfadiazine, sulfamerazine, sulfamethazine, and sulfamethoxazole); trimethoprim, an antibiotic that is frequently co-administered with sulfamethoxazole; amphenicols (chloramphenicol, florfenicol and thiamphenicol); fluoroquinolones (ciprofloxacin, enrofloxacin, flumequine, danofloxacin, gatifloxacin, norfloxacin, marbofloxacin and grepafloxacin); penicillins (amoxicillin); tetracyclines (chlortetracycline and oxytetracycline); non-steroidal anti-inflammatory drugs (salicylic acid and ibuprofen); beta-blocker drugs (atenolol); and antiepileptics (carbamazepine) were analysed. Ciprofloxacin, ibuprofen, salicylic acid, flumequine, and carbamazepine were detected and/or quantified at some of the selected sampling points. A clear ecotoxicological risk to the ecosystem was demonstrated from the occurrence of ciprofloxacin in samples obtained after the punctual and massive presence of people inside the Park. Furthermore, flumequine and carbamazepine have been detected in Procambarus clarkii specimens in concentrations around 30 ng g-1 and 14 ng g-1, respectively, and their occurrence in the specimens could indicate the persistence of the discharge sources. The main source of pharmaceuticals into the Park might be the livestock farming activities, and the influence of urban wastewaters from surrounding villages does not seem to be very important.

Citrate and Polyvinylpyrrolidone Stabilized Silver Nanoparticles as Selective Colorimetric Sensor for Aluminum (III) Ions in Real Water Samples.

The use of silver nanoparticles stabilized with citrate and polyvinylpyrrolidone as a sensor for aluminum ions determination is proposed in this paper. These non-functionalized and specific nanoparticles provide a highly selective and sensitive detection system for aluminum in acidic solutions. The synthesized nanoparticles were characterized by transmission electron microscopy. Surface plasmon band deconvolution analysis was applied to study the interaction between silver nanoparticles and aluminum ions in solution. The interaction band in the UV-visible region was used as an analytical signal for quantitation purposes. The proposed detection system offers an effective AND wide linearity range (0.1-103 nM), specificity for Al(III) in THE presence of other metallic ions in solution, as well as high sensitivity (limit of detection = 40.5 nM). The proposed silver-nanoparticles-based sensor WAS successfully used for detecting Al(III) in real water samples.

Direct capillary electrophoresis analysis of basic and acidic drugs from microliter volume of human body fluids after liquid-phase microextraction through nano-fibrous membrane.

In the present work, a disposable microextraction device with a polyamide 6 nano-fibrous supported liquid membrane (SLM) is employed for the pretreatment of minute volumes of biological fluids. The device is placed in a sample vial for an at-line coupling to a commercial capillary electrophoresis instrument with UV-Vis detection (CE-UV) and injections are performed fully automatically from the free acceptor solution above the SLM with no contact between the capillary and the membrane. Up to 4-fold enrichment of model basic (nortriptyline, haloperidol, loperamide, and papaverine) and acidic (ibuprofen, naproxen, ketoprofen, and diclofenac) drugs is achieved by optimizing the ratio of the donor to the acceptor solution volumes (16 to 4 µL, respectively). The actual setup enables SLM extractions from less than a drop of sample and is suitable for pretreatment of scarce human body fluids. Two unique methods are reported for efficient clean-up and enrichment of the basic and acidic drugs from capillary blood (formed as dried blood spot), serum, and urine samples, which enable their determination at therapeutic and/or toxic levels. The hyphenation of the SLM extraction with CE-UV analysis provides good repeatability (RSD, 2.4-14.9%), linearity (r2, 0.988-1.000), sensitivity (LOD, 0.017-0.22 mg L-1), and extraction recovery (ER, 20-106%) at short extraction times (10 min) and with minimum consumption of samples and reagents. Graphical abstract.

Chitosan tailor-made membranes as biopolymeric support for electromembrane extraction.

A chitosan membrane composed by 60% (w/w) chitosan and 40% (w/w) Aliquat®336 has been proposed as a new biopolymeric support for electromembrane extraction. The new support has been characterized by Scanning Electron Microscopy, resulting a 30-35 µm thickness. Amoxicillin, nicotinic acid, hippuric acid, salicylic acid, anthranilic acid, ketoprofen, naproxen and ibuprofen have been successfully extracted using the proposed support. Better enrichment factors were obtained for the acidic polar analytes than for the non-steroidal anti-inflammatory compounds (ranging from 118 for hippuric acid and 20 for ibuprofen). Electromembrane extraction was developed applying a DC voltage of 100 V, 1-octanol as supported liquid membrane and 20 min of extraction. The target analytes have also been satisfactorily extracted from human urine samples, providing high extraction efficiencies. The chitosan membrane is presented as a promising alternative for supporting liquid membrane compared to commonly used materials for this purpose.

On-chip electromembrane extraction of acidic drugs.

In the present work, a new supported liquid membrane (SLM) has been developed for on-chip electromembrane extraction of acidic drugs combined with HPLC or CE, providing significantly higher stability than those reported up to date. The target analytes are five widely used non-steroidal anti-inflammatory drugs (NSAIDs): ibuprofen (IBU), diclofenac (DIC), naproxen (NAX), ketoprofen (KTP) and salicylic acid (SAL). Two different microchip devices were used, both consisted basically of two poly(methyl methacrylate) (PMMA) plates with individual channels for acceptor and sample solutions, respectively, and a 25 µm thick porous polypropylene membrane impregnated with the organic solvent in between. The SLM consisting of a mixture of 1-undecanol and 2-nitrophenyl octyl ether (NPOE) in a ratio 1:3 was found to be the most suitable liquid membrane for the extraction of these acidic drugs under dynamic conditions. It showed a long-term stability of at least 8 hours, a low system current around 20 µA, and recoveries over 94% for the target analytes. NPOE was included in the SLM to significantly decrease the extraction current compared to pure 1-undecanol, while the extraction properties was almost unaffected. Moreover, it has been successfully applied to the determination of the target analytes in human urine samples, providing high extraction efficiency.

New nanostructured support for carrier-mediated electromembrane extraction of high polar compounds.

A new support has been proposed to be used for carrier-mediated electromembrane extraction purposes. The new support (Tiss®-OH) is a 100µm thickness sheet nanofiber membrane manufactured by electrospinning and composed by acrylic nanofibers. It has been used in an electromembrane extraction (EME) combined with a HPLC procedure using diode array detection. The proposed method has been used for the extraction of four high polarity acidic compounds: nicotinic acid, amoxicillin, hippuric acid and salicylic acid. Analytes were extracted from an aqueous sample solution (pH 4) (donor phase) using a Tiss®-OH sheet that supports a 5% (w/v) Aliquat®336 in 1-octanol liquid membrane. Aqueous solution (pH 6) was used as acceptor phase. The electrical field was generated from a d.c. electrical current of 100V through two spiral shaped platinum wires placed into donor and acceptor phases. Analytes were extracted in 10min with recoveries in the 60-85% range. The proposed EME procedure has been successfully applied to the determination of the target analytes in human urine samples.