Pharmacokinetics of the Recalcitrant Drug Lamotrigine: Identification and Distribution of Metabolites in Cucumber Plants.

Treated wastewater is an important source of water for irrigation. As a result, irrigated crops are chronically exposed to wastewater-derived pharmaceuticals, such as the anticonvulsant drug lamotrigine. Lamotrigine is known to be taken up by plants, but its plant-derived metabolites and their distribution in different plant organs are unknown. This study aimed to detect and identify metabolites of lamotrigine in cucumber plants grown for 35 days in a hydroponic solution by using LC-MS/MS (Orbitrap) analysis. Our data showed that 96% of the lamotrigine taken up was metabolized. Sixteen metabolites possessing a lamotrigine core structure were detected. Reference standards confirmed two; five were tentatively identified, and nine molecular formulas were assigned. The data suggest that lamotrigine is metabolized via N-carbamylation, N-glucosidation, N-alkylation, N-formylation, N-oxidation, and amidine hydrolysis. The metabolites LTG-N2-oxide, M284, M312, and M370 were most likely produced in the roots and were translocated to the leaves. Metabolites M272, M312, M314, M354, M368, M370, and M418 were dominant in leaves. Only a few metabolites were detected in the fruits. With an increasing exposure time, lamotrigine leaf concentrations decreased because of continuous metabolism. Our data showed that the metabolism of lamotrigine in a plant is fast and that a majority of metabolites are concentrated in the roots and leaves.

pH-induced homogeneous liquid-liquid microextraction method based on new switchable deep eutectic solvent for the extraction of three antiepileptic drugs from breast milk.

Aim: A pH-induced homogeneous liquid-liquid microextraction (HLLME) using a new switchable deep eutectic solvent has been used for the extraction of three antiepileptic drugs from breast milk samples. Methodology: This method is based on phase separation by changing pH. An ammonia solution and a phosphocholine chloride: hexanoic acid: p-aminophenol deep eutectic solvents were used as the phase separation agent and extraction solvent, respectively. Results: Significant factors were studied and the detection limits and enrichment factors were in the ranges of 0.009-0.19 ng ml-1 and 182-212 for the analytes, respectively. Also, linear ranges were wide (0.63-500 ng ml-1) and the method precision was acceptable. Conclusion: The introduced method was successfully applied for the determination of the analyte concentrations in breast milk samples.

Multiobjective optimization of microemulsion- thin layer chromatography with image processing as analytical platform for determination of drugs in plasma using desirability functions.

A new platform was developed for determination of drugs in plasma without extraction or instrumental analysis just using TLC, smart phone digital camera and free image processing software. Lamotrigine, antiepileptic drug was used as model analyte. The proposed platform depends on using oil-in-water (O/W) microemulsion to isolate the drug from plasma proteins and using water-in-oil (W/O) microemulsion as mobile phase for TLC which results in complete separation between lamotrigine and plasma as viewed under UV lamp. The composition of both microemulsions was optimized using Taguchi orthogonal array and Plackett- Burman design. The optimal (O/W) microemulsion predicted composition was 0.01 mL Butyl acetate, 4 mL butanol, 0.925 gm SDS and 8.6 mL water while the (W/O) mobile phase microemulsion was 9 mL Butyl acetate, 1 mL butanol, 0.25 gm SDS, 0.25 mL water. Separation was carried out on a silica gel 60F-254 plate eluted with the (W/O) microemulsion in about 30 min development time. The images of TLC plates were processed using 4 different programs, by comparing their results it was found that "integrated density" measured by Fiji software was the most accurate response that could measure the concentration of lamotrigine in spiked plasma in the range of (20-200) ng/spot. This method was applied also for determination of lamotrigine in lamictal® tablet dosage form using the same mobile phase. The precision of the method was satisfactory; the maximum value of relative standard deviations did not exceed 1.5%. While the accuracy was proved by the low values of % error and high values of recovery.

Ionic Liquid-Based Dispersive Liquidâ€"Liquid Microextraction for the Simultaneous Determination of Carbamazepine and Lamotrigine in Biological Samples.

This paper describes a new approach for the determination of carbamazepine and lamotrigine in biological samples by ionic liquid dispersive liquid-phase microextraction prior to high-performance liquid chromatography with ultraviolet detection. The effects of different ionic liquids (ILs) on the extraction efficiency of carbamazepine and lamotrigine were investigated. The highest extraction efficiencies of carbamazepine and lamotrigine were obtained using 30 ?L of 1-me-thyl-3-octylimidazolium hexafluorophosphate [C8MIM][PF6]. Several factors affecting the microextraction efficiency, such as the type and volume of extracting solvent, type and volume of disperser solvent, salt concentration, and pH of the sample solution have been optimized. The calibration plots were linear in the range of 0.1-20 mg L-1 for carbamazepine and 0.3-40 mg L-1 for lamotrigine with detection limits of 0.04 mg L-1 for carbamazepine and 0.07 mg L-1 for lamotrig-ine in plasma samples. The results confirm the suitability of the presented method as a sensitive method for the analysis of the target analytes in urine and plasma samples.

Comparison of plasma, saliva, and hair lamotrigine concentrations.

BACKGROUND: In some clinical situations (pregnancy, aging, drug resistance, toxicity), measurements of lamotrigine plasma levels may be reliable. Limited studies indicate that saliva and hair could be alternative sources for monitoring lamotrigine therapy. The drug content in hair can also be used to assess the history of drug therapy and to ascertain long-term patient compliance. The aims of this study were to 1) determine the correlations among plasma, saliva, and hair lamotrigine concentrations, 2) evaluate saliva as an alternative matrix for monitoring drug levels and 3) evaluate hair as a source of information on adherence to antiepileptic treatment and on the correlation of hair concentrations with clinical outcomes in patients with epilepsy. METHODS: Plasma, saliva, and hair lamotrigine concentrations were measured by liquid chromatography-tandem mass spectrometry in positive ionization mode. The study group (n = 85) was recruited among the epileptic patients at the Institute of Psychiatry and Neurology, Warsaw, Poland. RESULTS: Plasma concentrations were not influenced by sex, age, or the concomitant use of other antiepileptic drugs. Lamotrigine saliva and plasma concentrations were strongly correlated (r = 0.82, p < 0.001). Lamotrigine hair concentrations were correlated with the plasma concentrations (r = 0.53, p < 0.001) and daily dose in mg/kg (r = 0.23, p = 0.024). The analysis revealed no significant correlation between lamotrigine hair levels and the number of seizures in the previous 3 months (r = -0.1, p > 0.05). CONCLUSIONS: The lamotrigine saliva concentration is strongly correlated with its plasma level, and saliva can be used as an alternative matrix to plasma for monitoring. Lamotrigine can also be successfully measured in hair, and the drug levels in hair tend to be correlated with the levels in plasma. However, lamotrigine levels in hair may not correspond to clinical outcomes (i.e., seizure episodes).