aldicarb-sulfoxide and aldicarb-sulfone

The use of polypharmacy in the present day clinical therapy has made the identification of clinical drug-drug interaction risk an important aspect of drug development process. Although many drugs can be metabolized to sulfoxide and/or sulfone metabolites, seldom is known on the CYP inhibition potential and/or the metabolic fate for such metabolites.. The key objectives were: a) to evaluate the in vitro CYP inhibition potential of selected parent drugs with sulfoxide/sulfone metabolites; b) to assess the in vitro metabolic fate of the same panel of parent drugs and metabolites.. In vitro drug-drug interaction potential of test compounds was investigated in two stages; 1) assessment of CYP450 inhibition potential of test compounds using human liver microsomes (HLM); and 2) assessment of test compounds as substrate of Phase I enzymes; including CYP450, FMO, AO and MAO using HLM, recombinant human CYP enzymes (rhCYP), Human Liver Cytosol (HLC) and Human Liver Mitochondrial (HLMit). All samples were analysed by LC-MS-MS method.. CYP1A2 was inhibited by methiocarb, triclabendazole, triclabendazole sulfoxide, and ziprasidone sulfone with IC50 of 0.71 µM, 1.07 µM, 4.19 µM, and 17.14 µM, respectively. CYP2C8 was inhibited by montelukast, montelukast sulfoxide, montelukast sulfone, tribendazole, triclabendazole sulfoxide, and triclabendazole sulfone with IC50 of 0.08 µM, 0.05 µM, 0.02 µM, 3.31 µM, 8.95 µM, and 1.05 µM, respectively. CYP2C9 was inhibited by triclabendazole, triclabendazole sulfoxide, triclabendazole sulfone, montelukast, montelukast sulfoxide and montelukast sulfone with IC50 of 1.17 µM, 1.95 µM, 0.69 µM, 1.34 µM, 3.61 µM and 2.15 µM, respectively. CYP2C19 was inhibited by triclabendazole and triclabendazole sulfoxide with IC50 of 0.25 and 0.22, respectively. CYP3A4 was inhibited by montelukast sulfoxide and triclabendazole with IC50 of 9.33 and 15.11, respectively. Amongst the studied sulfoxide/sulfone substrates, the propensity of involvement of CY2C9 and CYP3A4 enzyme was high (approximately 56% of total) in the metabolic fate experiments.. Based on the findings, a proper risk assessment strategy needs to be factored (i.e., perpetrator and/or victim drug) to overcome any imminent risk of potential clinical drug-drug interaction when sulfoxide/sulfone metabolite(s) generating drugs are coadministered in therapy.

Topics: Acetates; Albendazole; Aldicarb; Biotransformation; Cyclopropanes; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Drug Interactions; Humans; Isoenzymes; Methiocarb; Microsomes, Liver; Piperazines; Quinolines; Risk Assessment; Sulfides; Sulfones; Sulfoxides; Thiazoles; Triclabendazole

The intentional and accidental poisoning of animals and people is a threat to public health and safety worldwide. Necropsies and histopathological examinations of 26 cats and 10 dogs poisoned by the carbamates aldicarb and carbofuran, confirmed by thin layer chromatography (TLC) and high performance liquid chromatography with diode-array detector (HPLC-DAD) were analysed, with variable post mortem interval and conservation of the carcass. Biological matrices were collected for toxicological and histopathological analyses. High performance liquid chromatography with diode-array detector (HPLC-DAD) was utilized to detect aldicarb and its metabolites, aldicarb sulphoxide and aldicarb sulphone, and carbofuran. The variable post mortem interval and the method of conservation of the carcass may be harmful to toxicological, necroscopic and histopathological analyses, that should be performed in order to provide reliable evidences to investigate possible poisoning of animals, which is cruel crime, and are usually linked to domestic or social conflict.

Topics: Aldicarb; Animals; Carbofuran; Cat Diseases; Cats; Dog Diseases; Dogs; Pesticides

A simple and rapid pretreatment procedure was developed for the simultaneous determination of aldicarb and its metabolites, aldicarb sulfone and aldicarb sulfoxide in ginger. The samples were extracted with acetonitrile, and then cleaned up with multiplug filtration using multiwalled carbon nanotubes (MWCNTS). The eluate was dried with nitrogen gas at room temperature, and redissolved in an acetonitrile-water (5:95, v/v) mixture, then quantified by ultra performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry (UPLC-ESI-MS/MS) operated in positive multiple reaction monitoring (MRM) mode. A linear relationship was achieved in the range of 0.5 -200 microg/L for the peak areas to the mass concentrations of the target compounds with the linear correlation coefficients (r2) higher than 0.99. The recoveries at three spiked levels of 2, 20 and 200 microg/kg were in the range from 71.4% to 89.8% with the relative standard deviations (RSDs, n = 6) from 0.7% to 13.2% under the selected conditions. The limits of quantification (LOQ, S/N = 10) of aldicarb, aldicarb sulfone, and aldicarb sulfoxide in ginger were 1.0, 2.0 and 1.0 microg/kg, respectively. The results demonstrate that the developed method is rapid, cost-effective, and can meet the requirements of the multiple pesticide residue analysis. The method is applicable to determine aldicarb and its metabolites in ginger.

Topics: Aldicarb; Nanotubes, Carbon; Pesticide Residues; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry; Zingiber officinale

Photocatalytic properties of fibers containing TiO2 nanoparticles were explored for use as a self-decontaminating material using degradation of the pesticide aldicarb as the model toxin. During the analysis of the aldicarb treated sample by liquid chromatography (LC) with diode array detector (DAD), an unidentified peak was found at relative retention time (RT) 3.9 min when compared to aldicarb and major metabolites, aldicarb sulfoxide, and aldicarb sulfone. An analytical method was developed to confirm and identify this degradation product. LC-APCI/MS techniques were used first to analyze molecular ions and major fragments comparing retention times and spectra with those of known standards. FTIR and LC-MS/MS techniques were used to confirm the identity of the degradation product as 2-propenal, 2-methyl-, O-[(methylamino)carbonyl]oxime.

Topics: Acrylic Resins; Aldicarb; Catalysis; Chromatography, High Pressure Liquid; Decontamination; Microchemistry; Molecular Structure; Nanocomposites; Nanostructures; Oximes; Pesticide Residues; Photolysis; Spectroscopy, Fourier Transform Infrared; Tandem Mass Spectrometry; Titanium; Ultraviolet Rays

The effect of four carbamates, aldicarb and its metabolites (aldicarb sulfone and aldicarb sulfoxide) and propoxur on glutathione content and the activity of the enzymes involved in the sulfur-redox cycle in the mammalian cellular model CHO-K1 cells after 24-h exposure were determined. Carbamate exposure resulted in a depletion of intracellular reduced glutathione (GSH) content, no change was observed in oxidized glutathione (GSSG) and a decrease in GSH/GSSG ratio was detected. After carbamates exposition a GSH/GSSG decreases in ranged from 12.44% to 21.35% of control was observed. Depletion of GSH levels was accompanied by the induction of glutathione reductase (GR) after 24h exposure with each of the four carbamates to CHO-K1 cells. After aldicarb sulfone, aldicarb sulfoxide, and propoxur exposure, glutathione peroxidase (GPx) activity increased in CHO-K1 cells by 198%, 32%, and 228% of control, respectively. After aldicarb sulfone and propoxur exposure, glutathione transferase (GST) activities increased by 49% and 230% of control, respectively. Due to the role played by GSH in preventing cytotoxicity via free-radical scavenging, results obtained suggest that high concentrations of aldicarb sulfone and propoxur closely resembling oxidative stress in CHO-K1 cells.

Topics: Aldicarb; Animals; Antioxidants; CHO Cells; Cricetinae; Cricetulus; Enzyme Induction; Glutathione; Glutathione Disulfide; Glutathione Peroxidase; Glutathione Reductase; Insecticides; Oxidative Stress; Propoxur

The metabolites of pesticides can contaminate groundwater and pose a risk to human health when this water is used for drinking. This paper reports the results of a laboratory study on aldicarb and its main metabolites, aldicarb sulfone and aldicarb sulfoxide. Aldicarb and its metabolites showed Koc values (6-31) which were lower than that of atrazine (55), indicating that they are very mobile in soil. They are less persistent than atrazine (DT50 = 25 days), with DT50 values from less than 1 day and up to 12 days. Aldicarb behaved as a non-leacher, whereas its metabolites clearly showed the characteristics of leachers. Aged residue leaching experiments showed that aldicarb can occur at high concentrations in the leachate, together with its two metabolites. The leachate composition depends on the incubation time of the parent compound. Aldicarb and its metabolites can form various mixtures in groundwater on the basis of the time elapsing between the application of the insecticide and the first significant rainfall. This study confirms the characteristics of contaminants of aldicarb and especially its metabolites, as reported in the literature.

Topics: Aldicarb; Algorithms; Atrazine; Bacteria; Clinical Laboratory Techniques; Colony Count, Microbial; Fresh Water; Herbicides; Insecticides; Kinetics; Molecular Structure; Pesticide Residues; Soil Pollutants; Time Factors; Water; Water Pollutants, Chemical; Water Pollution, Chemical; Water Supply

Topics: Aldicarb; California; Fresh Water; Pesticide Residues; Time Factors; Water Pollutants, Chemical; Water Supply

A screening method for the determination of aldicarb (AS) and its sulfoxide (ASX) and sulfone (ASN) metabolites in tobacco at low ppm levels is described. Tobacco samples are extracted using methanol with the aid of sonication at ambient conditions. The extract is filtered and then injected into a high-performance liquid chromatograph equipped with a dual post-column reaction system and a fluorescence detector. Chromatographic separation is performed on a C18 column with a mixture of methanol-acetonitrile-water containing 0.1% of triethanolamine as the mobile phase. Triethanolamine is added to improve peak shape of AS residues and to reduce the undesired interaction between residual silanols and interferences, mainly amino acids and other amines. The average recoveries for AS residues spiked in tobacco are higher than 95% for AS, 91% for ASN and 85% for ASX at levels of 0.5-10 ppm (w/w). The detection limit is 0.5 ppm for each of the target compounds.

Topics: Aldicarb; Chromatography, High Pressure Liquid; Nicotiana; Plants, Toxic; Spectrometry, Fluorescence

A reversed-phase high-performance liquid chromatographic (HPLC) method has been developed for the determination of trace concentrations of benomyl, carbendazim, aldicarb, aldicarb sulphoxide and aldicarb sulphone in drinking water. A 10-ml sample of water is passed through a 3-cm precolumn, packed with 5-microns C8 sorbent, at a flow-rate of 5 ml/min. The HPLC system is then switched to an acetonitrile-water gradient elution program. The preconcentrated analytes are eluted from, and separated by, the 3-cm C8 precolumn and determined by UV absorption. The total analytical time is 25 min. The lowest detectable concentrations are in the range of 2.5 x 10(-9)-11.0 x 10(-9) g/ml for the five analytes investigated with 10 ml of sample.

Topics: Aldicarb; Benomyl; Benzimidazoles; Carbamates; Chromatography, High Pressure Liquid; Fungicides, Industrial; Water

A method is described for the determination of aldicarb and its metabolites (the sulphoxide and sulphone) in urine by gas chromatography with flame photometric detection (GC-FPD). The sample was concentrated with a column containing activated charcoal and Florisil, and then eluted with dichloromethane-acetone (1:1, v/v). The aldicarb and aldicarb sulphoxide in the eluate solution were oxidized to aldicarb sulphone and the total sulphone concentration was determined by GC-FPD after extraction with dichloromethane and clean-up with an activated charcoal column. The detection limit was 0.0024 mg/l. The mean recoveries from spiked urine in the range 0.04-0.12 mg/l were 90.9%, 86.6%, 92.6% for aldicarb, aldicarb sulphoxide and aldicarb sulphone, respectively.

Topics: Aldicarb; Animals; Chromatography, Gas; Rats

A method is described for the analysis of aldicarb and its metabolites in urine by GC/FPD. The sample was concentrated with activated charcoal-Florisil column chromatography, eluted by dichloromethane-acetone (1:1v/v). The aldicarb, aldicarb sulfoxide in the eluted solution were oxidized by oxidizing reagent into aldicarb sulfone. The concentration of aldicarb sulfone was analyzed by GC/FPD. The detection limit of 0.0024 mg/L and coefficient of variation of 2.4%-7.4% were achieved. Mean recovery rates were 90.9%, 86.6%, 92.6% for aldicarb, aldicarb sulfoxide and aldicarb sulfone, respectively.

Topics: Aldicarb; Animals; Chromatography, Gas; Rats

Topics: Aldicarb; Animals; Daphnia; Insecticides; Lethal Dose 50; Water Pollutants; Water Pollutants, Chemical; Water Supply

A 1:1 mixture of aldicarb sulfoxide/aldicarb sulfone was administered to young adult Wistar rats via the drinking water at nominal concentrations of 19.2, 4.8, 1.2., 0.3, 0.075, or 0 ppm for 29 d. Blood was collected after 8, 15, and 29 d of treatment for plasma and erythrocyte cholinesterase determinations, and brain cholinesterase was determined at sacrifice. Body weight, food intake, and water consumption were measured weekly. Body weight gain and water consumption were reduced at 7, 14, 21, and 29 d in male and female rats at 19.2 ppm. Food consumption was reduced in males at 7, 14, 21, and 29 d but was reduced in females only on d 7. Both plasma and erythrocyte cholinesterase activity were reduced after 8, 15, and 29 d in male and female rats at 19.2 ppm. Males at 4.8 ppm showed reductions in plasma activity only after d 8 and in erythrocyte activity only after d 29. Female rats at 19.2 ppm also displayed depressions in brain cholinesterase activity not observed in similarly treated males. Since the only effects noted at 4.8 ppm were reductions in plasma and red blood cell cholinesterase activity in males only and at only one of three sampling periods, these two instances are not believed to be of any biological significance. The data suggest that 4.8 ppm in drinking water is a no observable ill-effect level for exposure of rats to aldicarb residues based on the parameters measured in this study.

Topics: Acetylcholinesterase; Aldicarb; Animals; Body Weight; Drinking; Eating; Erythrocytes; Female; Insecticides; Male; Rats; Rats, Inbred Strains; Water

Topics: Aldicarb; Gas Chromatography-Mass Spectrometry; Insecticides; Mass Spectrometry; Vegetables

The kinetics of degradation of aqueous solutions of aldicarb, aldicarb sulfoxide and aldicarb sul fone by base hydrolysis were investigated. Pseudo first order rate constants of 37 micrograms/l solutions were determined at different hydroxide concentrations by acid-base titration. Second order rate constants were calculated, and it was found that aldicarb sulfone is more sensitive to hydroxide ion concentration than aldicarb sulfoxide which is more sensitive than aldicarb. Temperature effects were determined by measuring the base hydrolysis rate constant for aldicarb sulfone at 5, 15, 20, 25, 30, and 35 degrees C. An activation energy of 15.2 +/- 0.1 kcal/mole was calculated. Addition of a neutral electrolyte decreased the rate constant for base hydrolysis. Acid catalyzed hydrolysis rate constants were also measured for aldicarb sulfone, and, as expected, the reaction was much slower. The second order (reaction) rate constant for base hydrolysis of aldicarb sulfone is 40.3 (+/- 0.5) liter mole-1min-1; for acid catalyzed hydrolysis it is 7.33 (+/- 0.06) X 10(-4) liter mole-1min-1.

Topics: Aldicarb; Hydrogen-Ion Concentration; Hydrolysis; Insecticides; Kinetics; Thermodynamics; Water Pollution, Chemical

An ion-suppression reverse phase high pressure liquid chromatographic method is described for the determination of aldicarb, aldicarb sulfoxide, and aldicarb sulfone in potatoes. Samples are extracted with methylene chloride and Na2SO4, evaporated to dryness, and cleaned up using Sep-Pak silica and Sep-Pak-C18 cartridges. The extract can be successfully analyzed by high pressure liquid chromatography on either a mu LiChrosorb RP-18 or mu Bondapak C18 column and quantitated using a variable wavelength ultraviolet detector set at either 220 or 247 nm. The mobile phase is acetonitrile-buffer (4 + 96) and (30 + 70), buffered to pH 7.6 and flowing at 2 mL/min. Recoveries ranged from 80 to 100%. The minimum detectable amount was 37.5 ng, which easily permitted the quantitation of 0.1 ppm aldicarb sulfone in 75 g sample. The recovery of aldicarb was low because of its rapid enzymatic oxidation to aldicarb sulfoxide and sulfone.

Topics: Aldicarb; Chromatography, High Pressure Liquid; Food Contamination; Hydrogen-Ion Concentration; Insecticides; Spectrophotometry, Ultraviolet; Vegetables