Gelatin microsphere coated Fe3O4@graphene quantum dots nanoparticles as a novel magnetic sorbent for ultrasound-assisted dispersive magnetic solid-phase extraction of tricyclic antidepressants in biological samples.

Gelatin microsphere-coated Fe3O4@graphene quantum dots (Fe3O4@GQD@GM) were designed and synthesized as a novel sorbent via ultrasonic-assisted dispersive magnetic solid-phase extraction (UA-DMSPE) method. The synthesized sorbent was identified and confirmed by FT-IR, XRD, VSM, and SEM techniques. UA-DMSPE was combined with corona discharge ion mobility spectrometry for trace determination of desipramine, sertraline, and citalopram. Effective parameters were considered and optimized. The proposed method, under optimal conditions, showed excellent linearity in different concentration ranges (2-700 ng mL-1, R2 > 0.995), repeatability (RSD < 5.1%), good sensitivity (LODs in the range 0.6-1.5 ng mL-1), high preconcentration factor (PF = 207-218), and acceptable relative recoveries (93.5-101.8%). Eventually, this method was used to determine tricyclic antidepressants in various biological samples. Schematic presentation of the microextraction and monitoring of TCAs by ultrasonic-assisted dispersive magnetic solid phase microextraction-ion mobility spectrometry producer.

Carbon Nanohorn Suprastructures on a Paper Support as a Sorptive Phase.

This article describes a method for the modification of paper with single-wall carbon nanohorns (SWCNHs) to form stable suprastructures. The SWCNHs form stable dahlia-like aggregates in solution that are then self-assembled into superior structures if the solvent is evaporated. Dipping paper sections into a dispersion of SWCNHs leads to the formation of a thin film that can be used for microextraction purposes. The coated paper can be easily handled with a simple pipette tip, paving the way for disposable extraction units. As a proof of concept, the extraction of antidepressants from urine and their determination by direct infusion mass spectrometry is studied. Limits of detection (LODs) were 10 ng/L for desipramine, amitriptyline, and mianserin, while the precision, expressed as a relative standard deviation, was 7.2%, 7.3%, and 9.8%, respectively.

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.

Determination of desipramine in biological samples using liquid-liquid-liquid microextraction combined with in-syringe derivatization, gas chromatography, and nitrogen/phosphorus detection.

A method was established for the determination of desipramine in biological samples using liquid-liquid-liquid microextraction followed by in-syringe derivatization and gas chromatography-nitrogen phosphorus detection. The extraction method was based on the use of two immiscible organic solvents. n-Dodecane was impregnated in the pores of the hollow fiber and methanol was placed inside the lumen of the fiber as the acceptor phase. Acetic anhydride was used as the reagent for the derivatization of the analyte inside the syringe barrel. Parameters that affect the extraction efficiency (composition of donor and acceptor phase, ionic strength, sample temperature, and extraction time) as well as derivatization efficiency (amount of acetic anhydride and reaction time and temperature) were investigated. The limit of detection was 0.02 µg/L with intra and interday RSDs of 2.6 and 7.7%, respectively. The linearity of the method was in the range of 0.2-20 µg/L (r(2) = 0.9986). The method was successfully applied to determine desipramine in human plasma and urine.

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.

A green and low-cost method employing switchable hydrophilicity solvent for the simultaneous determination of antidepressants in human urine by gas chromatography - mass spectrometry detection.

In this study, the use of switchable hydrophilicity solvent with a simple and low-cost lab-made device for the extraction procedure in homogeneous liquid-liquid microextraction is proposed for the first time in the determination of antidepressants in human urine. The antidepressants studied consisted of fluoxetine, amitriptyline, nortriptyline, imipramine, desipramine and sertraline. The optimization of the main parameters that can influence on the extraction efficiency was performed through multivariate approaches. The analytes were separated and identified by gas chromatography coupled to mass spectrometry (GC-MS). The optimal extraction conditions consisted of using N,N-dimethylcyclohexylamine (DMCHA) as the switchable hydrophilicity solvent (SHS), 500 µL of urine sample previously diluted with ultrapure water at 1:1 ratio (v/v), 200 µL of a mixture of SHS:HCl 6 mol L-1 (1:1 v/v), 600 µL of NaOH 10 mol L-1 and 3 min of extraction time. A volume of 40 µL of diphenylamine at concentration of 500 µg L-1 (20 ng) was used as internal standard. The method developed was in-house validated, providing coefficients of determination higher than 0.995 for all analytes, limits of detection (LOD) from 0.02 to 0.88 µg L-1, limits of quantification (LOQ) from 0.05 to 2.92 µg L-1, relative recoveries of 68 to 102%, intra-day precision from 0.5 to 15.9%, inter-day precision from 4.2 to 19.3%, selectivity and robustness. The method proposed was successfully applied in five human urine samples from a Toxicological Information Center located in Porto Alegre (Brazil). The results demonstrated that the µP-SHS-HLLME approach is highly cost-effective, rapid, simple and environmentally-friendly with satisfactory analytical performance.

Fast urinary screening for imipramine and desipramine using on-line solid-phase extraction and selective derivatization.

A continuous-flow configuration based on sequential solid-phase extraction and derivatization is proposed for the screening of urine samples for imipramine and related metabolites. For the first time, a 50/50 (v/v) methanol/nitric acid mixture is used as both eluent and derivatizing reagent. Sample aliquots are injected into the flow manifold and driven by a water stream to an RP-C(18) column where the drugs are quantitatively retained. Following clean-up step with 40/60 (v/v) methanol/water, the eluent/derivatizing reagent is injected and passed through the sorbent column, eluted drugs reacting with nitric acid to form a blue dye that is monitored at 600 nm. The global signal thus obtained for the antidepressants can be used to estimate their total concentration in the samples without the need to individually quantify the analytes. This total index can be used for timely decision-making in case of overdosage. The proposed method is sensitive and selective; thus, typical interferents such as endogenous and diet compounds have no substantial effect on the analytical signal. This allows imipramine and its metabolites to be determined at therapeutic levels in urine samples.

Phenotypic consistency in hydroxylation of desmethylimipramine and debrisoquine in healthy subjects and in human liver microsomes.

The 2-hydroxylation of desmethylimipramine (DMI) and the 4-hydroxylation of debrisoquine (D) were studied in healthy subjects and in human liver microsomes. A single oral dose of DMI (25 mg) was given to 18 healthy subjects previously phenotyped with D (13 rapid and five slow hydroxylators). Urine was collected for 24 hr and DMI and total 2-hydroxydesmethylimipramine (2-OH-DMI) levels were determined by HPLC. The urinary ratio DMI/2-OH-DMI correlated strongly (r = 0.92) with the urinary ratio of D to 4-hydroxydebrisoquine (D/4-OH-D). The two hydroxylations were also studied in human liver microsomes from 10 different subjects. Formation rates of the hydroxylated metabolites correlated strongly (r = 0.869). Moreover, D competitively inhibited the 2-hydroxylation of DMI. These findings suggest that both are hydroxylated by the same cytochrome P-450 isozyme.

Variability in metabolism of imipramine and desipramine using urinary excretion data.

Variability in imipramine and desipramine metabolism was evaluated using urinary excretion data from patients with pain. Liquid chromatography-tandem mass spectrometry was used to quantitate concentrations in urine specimens. Interpatient population contained 600 unique imipramine specimens, whereas intrapatient population had 137 patients with two or more specimens. Normal concentration ranges of imipramine, desipramine and the desipramine/imipramine metabolic ratio (MR) were established, and various factors were tested for MR impact. Geometric mean of imipramine urine concentration was 0.46 mg/g of creatinine, and desipramine was 0.67 mg/g of creatinine. Gender, concomitant known CYP2C19 inhibitor use and urine pH did not affect MR. However, proton-pump inhibitor (PPI) users had a significantly lower mean MR than those without a listed PPI. Early age group (18-36 years) had a significantly higher mean MR than middle (37-66 years) and late (67-90 years) age groups. Approximately one-third were positive for one or more of hydrocodone, oxycodone, hydromorphone or oxymorphone. Patients with no opioids reported in the medication list had a significantly lower geometric mean MR than those with prescribed opioids (1.03 vs. 1.54, P = 0.004). Patients with only one prescribed opioid had a lower MR than those with two or more prescribed opioids. Patients with younger age, prescribed opioids and no listed PPI were more likely to have a higher geometric mean urinary desipramine/imipramine MR.

Effects of desvenlafaxine on the pharmacokinetics of desipramine in healthy adults.

The results of two single-center, two-period, open-label trials that evaluated the effects of multiple doses of desvenlafaxine on the pharmacokinetics of desipramine, a cytochrome P450 (CYP) 2D6 enzyme substrate, are presented. Healthy individuals aged 18-45 years were administered a single oral dose of 50 mg desipramine with and without 100 mg daily (n=34) or 400 mg daily (n=23) desvenlafaxine for 5 days. After coadministration of 100 mg desvenlafaxine, desipramine exposure, measured by peak plasma concentration (C(max)) and total area under the plasma concentration-versus-time curve (AUC), showed minimal increases of 25 and 17%, respectively; coadministration of 400 mg desvenlafaxine resulted in a 52% increase in desipramine C(max) and a 90% increase in AUC. For the 100 mg dose, the geometric least squares mean ratios and 90% confidence intervals (CIs) for desipramine AUC (117%; 90% CI 110-125%), 2-hydroxydesipramine AUC (114%; 90% CI 110-119%), and C(max) (110%; 90% CI 104-116%) were all within the 80-125% interval, showing the bioequivalence for AUC between desipramine administered alone and in combination with 100 mg desvenlafaxine. These results indicate that desvenlafaxine is a relatively weak inhibitor of CYP2D6 and that desvenlafaxine 100 mg, twice the recommended therapeutic dose of 50 mg, is unlikely to cause drug-drug interactions with CYP2D6 substrates.

Isolation and identification of the glucuronide conjugate of 2-hydroxydesipramine by preparative liquid chromatography.

A semi-preparative column liquid chromatographic procedure for the isolation and purification of milligram quantities of the glucuronide conjugate of 2-hydroxydesipramine, a major metabolite of desipramine, is presented. Urine from patients receiving desipramine was collected and passed through a column of XAD-2 resin. The methanolic extract was chromatographed on a reversed-phase octadecyl semi-preparative column followed by further purification on a silica gel column of the same dimension, yielding a product 95% pure. Fast atom bombardment and thermospray mass spectroscopy, as well as ultraviolet photodiode-array spectroscopy and hydrolysis with beta-glucuronidase confirmed the identification and purity of 2-hydroxydesipramine glucuronide. This important glucuronide metabolite will be a useful tool as an authentic standard for pharmacokinetic and metabolism studies and for determining its pharmacological characteristics in laboratory animals.

High-performance liquid chromatography of imipramine and six metabolites in human plasma and urine.

A method for the simultaneous quantitation of imipramine and six metabolites (2- and 10-hydroxyimipramine, 2- and 10-hydroxydesipramine, didesmethylimipramine and desipramine) in human plasma and urine has been developed. The method is based on a three-step liquid-liquid extraction followed by isocratic, reversed-phase high-performance liquid chromatography with ultraviolet absorbance detection (detection wavelength: 220 nm). The chromatographic eluent consisted of 30% acetonitrile and 70% aqueous sodium perchlorate solution pH 2.5. Glucuronide conjugates in urine were deconjugated with beta-glucuronidase/arylsulphatase prior to extraction.

Urinary desipramine hydroxylation index and steady-state plasma concentrations of imipramine and desipramine.

An index of desipramine (DMI) hydroxylation, calculated as the ratio between the amounts of DMI and 2-hydroxydesipramine (2-OH-DMI) excreted in urine after 25 mg orally, was determined in 16 depressed patients. The index varied almost 100-fold between the patients and correlated significantly to the steady-state plasma concentrations of DMI (rs = 0.85; p less than 0.01) but not to the plasma levels of imipramine (IMI) when the patients were treated with 75 mg of IMI daily. Eleven of the 16 patients were subsequently treated with DMI and a significant relationship was again found between the plasma levels of DMI and the urinary DMI-hydroxylation index (rs = 0.87; p less than 0.01). The latter may be utilized in therapeutic drug monitoring to identify individuals with unusually rapid or slow hydroxylation of DMI.

A sensitive colorimetric method for the determination of imipramine hydrochloride and desipramine hydrochloride.

A simple and rapid colorimetric method for the determination of imipramine hydrochloride and desipramine hydrochloride in their tablet formulations and in biological fluids is presented. The method is based on the reaction of these drugs with 3-methyl-2-benzothiazolone hydrazone in the presence of ferric chloride, with direct measurement at 635 nm. Cyclohexane was used to extract these drugs from serum and urine, at basic pH, by a single manual extraction. The method can detect 0.5 microgram/ml of each drug. The main advantages of this method are its simplicity and high sensitivity.

Effects of specific antibody Fab fragments on desipramine pharmacokinetics in the rat in vivo and in the isolated, perfused liver.

Drug-specific antibody fragments, which can reverse tricyclic antidepressant toxicity in rats, represent a potential clinical treatment for tricyclic antidepressant overdose in humans. To delineate the pharmacokinetic mechanisms, we studied the effects of a high-affinity, drug-specific Fab fragment on desipramine (DMI) disposition in rats and on DMI kinetics in the isolated, perfused rat liver. These studies were performed at high DMI and Fab doses, with Fab administered at the time of peak DMI toxicity, to simulate the treatment of overdose. Rats received 20 mg/kg DMI intravenously over 30 min followed in 10 min by DMI-specific ovine polyclonal Fab (DMI-Fab) or nonspecific human Fab (control-Fab) (1.1 g/kg; molar Fab-to-DMI ratio, 0.34) intravenously over 20 min. The serum DMI concentration increased by 50-fold 5 min after DMI-Fab administration. The mean area under the serum concentration-time curve increased by more than 3-fold. The steady-state volume of distribution was decreased by 90% and total body clearance was decreased by 70% after DMI-Fab administration compared with control-Fab. Renal clearance increased by 72% after DMI-Fab and total renal excretion of DMI increased by 7-fold due to the much higher serum DMI concentration. Ninety-four percent of DMI-Fab excretion and 87% of DMI excretion occurred in the first 12 h. The percent of DMI bound in urine was markedly increased by DMI-Fab (87.1 vs. 19.1%), as was the molar ratio of DMI to DMI-Fab in urine (0.75 vs. 0.08). Isolated rat livers were perfused with DMI alone, DMI and DMI-Fab or DMI and control-Fab.(ABSTRACT TRUNCATED AT 250 WORDS)