Evaluation of dispersive liquid-liquid microextraction by coupling with green-based agarose gel-electromembrane extraction: An efficient method to the tandem extraction of basic drugs from biological fluids.

Nowadays, developing new methods for the effective extraction/separation of drugs (present at trace levels) from complicated matrices (as biological fluids) is certainly a great challenge for many operators. In this regard, green-based agarose gel electromembrane extraction (G-EME) was for the first time combined with dispersive liquid-liquid microextraction (DLLME) toward G-EME/DLLME methodology (i.e., tandem extraction approach). Two basic drugs such as trimipramine (TRI) and clomipramine (CLO) extracted from the urine samples, were used as model compounds. Regarding method workflow, analytes were extracted from the 5 mL sample, through a synthesized agarose gel membrane, to the 700 µL aqueous acceptor phase under the optimized conditions (pH of acceptor phase: 2.0; pH of gel membrane: 2.0; pH of donor phase: 4.0, voltage value: 30 V, and extraction time: 25 min). In the next step, acceptor solution was poured to a conic vial and mixed with 100 µL alkaline solution (NaOH, 1 M). Afterwards, DLLME procedure took place again at optimal conditions, i.e., extraction solvent was carbon tetrachloride (10 µL), and dispersive solvent was acetone (100 µL). Ultimately, gas chromatography (GC) was applied for the detection and quantification of drugs. Such G-EME/DLLME configuration has brought two main advantages. Firstly, interferences such as proteins and other large biological molecules were eliminated from biological fluids via G-EME. Further, high enrichment factors (EFs of 260-370 refer to extraction recoveries of 52-74%) were obtained using DLLME with acceptable detection limits (1.0-3.0 ng mL-1). Finally, the suggested approach was successfully utilized to determine drugs at trace levels in urine samples.

A new carbon paste electrode modified with MWCNTs and nano-structured molecularly imprinted polymer for ultratrace determination of trimipramine: The crucial effect of electrode components mixing on its performance.

A novel carbon nanocomposite paste electrode was prepared and used as a voltammetric sensor for ultratrace determination of trimipramine (TRI) which currently used for the treatment of psychiatric disorders. For this aim, nanoparticles of molecularly imprinted polymer (MIP), synthesized by precipitation polymerization method, and multi-walled carbon nanotubes (MWCNTs) were embedded in a nanocomposite paste electrode. The nanocomposite mixing style demonstrated a significant influence on the final electrode performance. The sensor exhibited linear response range of 1.0 × 10-10-2.5 × 10-8 mol L-1 and very high sensitivity of 2131 µA µâ€¯mol L-1. The lower detection limit of the sensor was calculated to be 4.5 × 10-11 mol L-1 (S/N = 3). This sensor was applied successfully for highly selective determination of TRI in pharmaceutical formulations, urine and serum samples without applying any sample pretreatment.

Electromembrane extraction through a virtually rotating supported liquid membrane.

Electromembrane extraction (EME) of model analytes was carried out using a virtually rotating supported liquid membrane (SLM). The virtual (nonmechanical) rotating of the SLM was achieved using a novel electrode assembly including a central electrode immersed inside the lumen of the SLM and five counter electrodes surrounding the SLM. A particular electronic circuit was designed to distribute the potential among five counter electrodes in a rotating pattern. The effect of the experimental parameters on the recovery of the extraction was investigated for verapamil (VPL), trimipramine (TRP), and clomipramine (CLP) as the model analytes and 2-ethyl hexanol as the SLM solvent. The results showed that the recovery of the extraction is a function of the angular velocity of the virtual rotation. The best results were obtained at an angular velocity of 1.83 RadS(-1) (or a rotation frequency of 0.29 Hz).The optimization of the parameters gave higher recoveries up to 50% greater than those of a conventional EME method. The rotating also allowed the extraction to be carried out at shorter time (15 min) and lower voltage (200 V) with respect to the conventional extraction. The model analytes were successfully extracted from wastewater and human urine samples with recoveries ranging from 38 to 85%. The RSD of the determinations was in the range of 12.6 to 14.8%.

High performance liquid chromatographic determination of ultra traces of two tricyclic antidepressant drugs imipramine and trimipramine in urine samples after their dispersive liquid-liquid microextraction coupled with response surface optimization.

Dispersive liquid-liquid microextraction (DLLME) coupled with high performance liquid chromatography by ultraviolet detection (HPLC-UV) as a fast and inexpensive technique was applied to the determination of imipramine and trimipramine in urine samples. Response surface methodology (RSM) was used for multivariate optimization of the effects of seven different parameters influencing the extraction efficiency of the proposed method. Under optimized experimental conditions, the enrichment factors and extraction recoveries were between 161.7-186.7 and 97-112%, respectively. The linear range and limit of detection for both analytes found to be 5-100ng mL(-1) and 0.6ng mL(-1), respectively. The relative standard deviations for 5ng mL(-1) of the drugs in urine samples were in the range of 5.1-6.1 (n=5). The developed method was successfully applied to real urine sample analyses.

Adsorptive stripping voltammetric determination of imipramine, trimipramine and desipramine employing titanium dioxide nanoparticles and an Amberlite XAD-2 modified glassy carbon paste electrode.

An Amberlite XAD-2 (XAD2) and titanium dioxide nanoparticles (TNPs) modified glassy carbon paste electrode (XAD2-TNP-GCPE) was developed for the determination of imipramine (IMI), trimipramine (TRI) and desipramine (DES). The electrochemical behavior of these molecules was investigated employing cyclic voltammetry (CV), chronocoulometry (CC), electrochemical impedance spectroscopy (EIS) and adsorptive stripping differential pulse voltammetry (AdSDPV). After optimization of analytical conditions using a XAD2-TNP-GCPE electrode at pH 6.0 phosphate buffer (0.1 M), the peak currents were found to vary linearly with its concentration in the range of 1.30 × 10(-9) to 6.23 × 10(-6) M for IMI, 1.16 × 10(-9) to 6.87 × 10(-6) M for TRI and 1.43 × 10(-9) to 5.68 × 10(-6) M for DES. The detection limits (S/N = 3) of 3.93 × 10(-10), 3.51 × 10(-10) and 4.35 × 10(-10) M were obtained for IMI, TRI and DES respectively using AdSDPV. The prepared modified electrode showed several advantages such as a simple preparation method, high sensitivity, very low detection limits and excellent reproducibility. The proposed method was employed for the determination of IMI, TRI and DES in pharmaceutical formulations, blood serum and urine samples.

Electromembrane extraction combined with cyclodextrin-modified capillary electrophoresis for the quantification of trimipramine enantiomers.

A sensitive, simple and reproducible method was developed for preconcentration and determination of trimipramine (TPM) enantiomers in biological samples using electromembrane extraction combined with cyclodextrin-modified capillary electrophoresis (CE). During the extraction, TPM enantiomers migrated from a 5 mL sample solution through a thin layer of 2-nitrophenyl octyl ether NPOE immobilized in the pores of a hollow fiber, and into a 20 µL acidic aqueous acceptor phase presented inside the lumen of the fiber. A Box-Behnken design and the response surface methodology (RSM) were used for the optimization of different variables on extraction efficiency. Optimized extraction conditions were: NPOE as supported liquid membrane, inter-electrode distance of 5 mm, stirring rate of 1000 rpm, 51 V potential difference, 34 min as the extraction time, acceptor phase pH 1.0 and donor phase pH 4.5. Then, the extract was analyzed using optimized cyclodextrin (CD)-modified CE method for the separation of TPM enantiomers. Best results were achieved using 100 mM phosphate running buffer (pH 2.0) containing 10 mM α-CD as the chiral selector, applied voltage of 18 kV and 20°C. The range of quantitation for both enantiomers was 20-500 ng/mL. The method was very reproducible so that intra- and interday RSDs (n=6) were <6%. The limits of quantitation and detection for both enantiomers were 20 and 7 ng/mL, respectively. Finally, this method was successfully applied to determine the concentration of TPM enantiomers in plasma and urine samples without any pre-treatment.

Electrospray ionization-ion mobility spectrometry as a detection system for three-phase hollow fiber microextraction technique and simultaneous determination of trimipramine and desipramine in urine and plasma samples.

A novel method based on three-phase hollow fiber microextraction technique (HF-LPME) coupled with electrospray ionization-ion mobility spectrometry (ESI-IMS) was developed for the simultaneous determination of two antidepressant drugs (trimipramine and desipramine) in urine and plasma samples. The effects of various parameters such as type of organic solvent, composition of donor and acceptor phase, stirring rate, salt addition, extraction time, and temperature were investigated. Under the optimized conditions, the relative standard deviation was in the range of 5-6%, and the method quantitation limit (MQL) of utilizing HF-LPME/ESI-IMS was 5 µg/L for both drugs. The relative recoveries obtained by the proposed method from urine and plasma samples were in the range 94% to 97% for trimipramine and 92% to 96% for desipramine. Finally, the feasibility of the proposed method was successfully confirmed by extraction and determination of trace amounts of trimipramine and desipramine in biological samples without any significant matrix effect.

Radiopaque stomach contents in postmortem CT in suicidal oral medication intoxication: report of three cases.

In clinical medicine, plane radiography is used for detecting the remains of medications in the stomach in oral medication intoxication cases. Since postmortem computed tomography (CT), performed prior to autopsy, is currently intensively entering the forensic routine, the technique was applied to three fatal cases of oral medication intoxication. Here we report CT and autopsy findings for these cases. In all three cases, hyperdense areas within the stomach content were documented. The measurement of Hounsfield Units (HU) beyond 74HU showed mean values of 338, 88 and 98HU. Postmortem CT also showed brain edema and pulmonary aspiration in one case. At autopsy, tablet remains in the stomach were detected microscopically in all three cases. The ex vivo CT scans of the ingested medicaments showed similar HU values. Despite the fact that further case studies are necessary beyond this one, and in spite of its limitations, postmortem CT was found to be a useful screening and documentation method for stomach contents in oral medication intoxication.

Metabolism of antidepressants: urinary metabolites of trimipramine in the rat.

1. Studies on the metabolism of the tricyclic antidepressant trimipramine (TMP) in the rat are described. 2. Twenty metabolites of TMP were isolated from rat urine after enzymatic hydrolysis and their structures were determined by a gas chromatographic-mass spectrometric (GC-MS) method. 3. Twelve TMP metabolites were the result of alicyclic (C10 or C11) oxidation in addition to the other metabolic pathways.

The metabolism of trimipramine in the rat.

Studies on the metabolism of the tricyclic antidepressant trimipramine, 5-(3-dimethylamino-2-methylpropyl)-10,11-dihydro-5H-dibenz[b,f]azepine, in the rat are described. Many metabolites of trimipramine (TMP) were isolated from rat urine after enzymatic hydrolysis and their structures were identified by a gas chromatographic/mass spectrometric method, before and after appropriate chemical derivatization. Besides unchanged TMP, 20 metabolites were characterized (underivatized, and after acetylation), of which 12 had undergone alicyclic (C10 or C11) oxidation. This is a hitherto unreported metabolic pathway for TMP in the rat.

Metabolism of trimipramine in man.

This paper describes studies on the metabolism of the tricyclic antidepressant 5-(3-dimethylamino-2-methylpropyl)-10,11-dihydro-5H-dibenz[b,f]azepine (trimipramine, Stangyl) in man. The metabolites were identified after cleavage of conjugates, extraction and derivatisation by acetylation in human urine using gas chromatography-mass spectrometry. Besides the unchanged trimipramine (T), the following 15 metabolites could be identified: mono- and dihydroxy-T, hydroxy-methoxy-T; iminodibenzyl (I), mono- and dihydroxy-I, hydroxy-methoxy-I; nor-T (NT), mono- and dihydroxy-NT, hydroxy-methoxy-NT; bis-nor-T (BNT), mono- and dihydroxy-BNT and hydroxy-methoxy-BNT. Therefore 3 overlapping metabolic pathways can be postulated: N-dealkylation of the nitrogen in the iminodibenzyl ring, 1- and 2-fold N-demethylation of the nitrogen in the side chain and 1- and 2-fold aromatic hydroxylation of the iminodibenzyl ring. The dihydroxy metabolites are partly methylated at one of the hydroxy groups. The hydroxy metabolites are conjugated additionally.