Magnetic solid-phase extraction for determination of sulpiride in human urine and blood using high-performance liquid chromatography.

A novel and efficient sample preconcentration technique based on the Fe3O4 magnetic nanoparticles (Fe3O4 MNPs) coated with silica (SiO2) has been developed for extraction and determination of sulpiride. The functionalized MNPs showed excellent dispersibility in aqueous solution and were applied to magnetic solid-phase extraction of sulpiride from human urine and blood prior to high-performance liquid chromatography analysis. The separation, preconcentration and desorption procedure was completed in 10 min. Optimal experimental conditions, including sample pH, the amount of the MNPs, eluent type and volume, and the ultrasonication time were studied and established. The method showed good linearity for the determination of sulpiride in the concentration range of 10-1000 ng/mL in urine and blood. The recovery of the method was in the range between 91.2 and 97.5%, and the limit of detection was 2 ng/mL for sulpiride in human blood and urine. The results indicated that the present procedure is a suitable pretreatment method for biological samples.

False-positive buprenorphine by CEDIA in patients prescribed amisulpride or sulpiride.

Buprenorphine is a potent partial opioid agonist that is analyzed in urine to (i) monitor adherence to maintenance or detoxification therapy and (ii) detect illicit use. Buprenorphine analysis is commonly conducted on urine by immunoassay, but is subject to cross-reactivity from other drugs/drug metabolites, including morphine, codeine and dihydrocodeine. This study reports false-positive buprenorphine analysis [Thermo Fisher Scientific cloned enzyme donor immunoassay (CEDIA)] in patients who denied unauthorized buprenorphine use prior to sampling, but who had been prescribed amisulpride. In two cases, confirmatory analysis by liquid chromatography-tandem mass spectrometry was negative (<0.5 µg/L) for buprenorphine and metabolites and positive for amisulpride. Although the cross-reactivity of amisulpride and sulpiride in the CEDIA buprenorphine assay is low (estimated at 0.003 and 0.002%, respectively), it remains a significant consideration given the likely high concentrations of these compounds in urine relative to the low cutoff of the buprenorphine assay. Neither amisulpride nor sulpiride was listed as potential sources of interference on the CEDIA data sheet when this work was performed. These findings highlight the importance of confirming immunoassay-positive buprenorphine results using a more selective analytical technique.

[Sulpiride poisoning--case report confirmed with the quantitative determination of the xenobiotic serum level]. / Zatrucie sulpirydem--opis przypadku potwierdzony ilosciowym oznaczeniem stezenia ksenobiotyku w surowicy.

Despite above 40 years the presence of sulpride on the pharmaceutical market, the acute poisonings are poorly reported in the medical literature. The discussed case of sulpiride intoxication concerns ingestion probably dose of 12 g, that exceeded 10-fold maximum therapeutic dose. 16-year-old girl, with no previous sulpiride treatment, was admitted to the Toxicology Department about 3 hours after ingestion. In clinical picture she presented quantitative consciousness disturbances with maximum 10 scores in GCS scale, with tendency to low BP (minimum 88/45 mmHg) and episode of orthostatic hypotension. The ECG demonstrated: normogram, sinus tachycardia with a heart rate of 125 beats/min, PQ = 120 ms, QRS = 80 ms, prolongation of QTc to 519,6 ms and unspecific changes of ST-T syndrome. The qualitative toxicological test confirmed the presence of chlorprothixene in urine, but the serum therapeutic concentration (0.126 microg/ml) excluded the overdose. The quantitative determination of sulpiride serum concentration confirmed acute sulpiride poisoning. The measured sulpiride toxic concentration on admission and in the consecutive hours were from 13.2 to 8.2 microg/ml. Sulpiride toxicokinetic parameters such as t max = about 3 h, t 1/2 = 24.02 h, k(el) = 0.029 h(-1) were also estimated. They point out that the absorption rate is similar and the elimination is prorogated in sulpiride acute poisoning compared to therapeutic doses.

Efficacy of surface charge in targeting pegylated nanoparticles of sulpiride to the brain.

The objective of the study was to formulate sulpiride-loaded nanoparticles (NPs) that can improve bioretention and achieve dose reduction by passively targeting the drug near the site of action. Methoxy PEG-PLA and maleimide PEG-PLA were synthesized via ring opening polymerization of L-lactide and used to prepare pegylated nanoparticles (NPs) loaded with sulpiride by emulsification and solvent evaporation method. Thiolated cationized bovine serum albumin (CBSA) was conjugated through the maleimide function to the NPs. Rhodamine B and Alexa Fluor 488 were used as fluorescent markers for nanoparticle uptake studies. The nanoparticles were characterized for particle size, zeta potential and drug loading. Sprague Dawley rats were administered with each of CBSA-NPs, BSA-NPs and uncoated NPs (10mg/kg) via tail vein; plasma and urine concentrations were measured and tissue sections were observed under fluorescence microscope. Characterized particles (mean particle size 329+/-44 nm) indicated the conjugation of cationic albumin to NPs (zeta potential shift from -39 mV to -19 mV). Fluorescence showed a high accumulation of CBSA-NPs in brain compared to that of BSA-NPs and uncoated NPs supported by plasma and urine profile. The significant results proved that CBSA-NPs could be a promising brain drug delivery for sulpiride.

Determination of sulpiride in human urine using excitation-emission matrix fluorescence coupled with second-order calibration.

This paper proposes a new and effective approach for the quantitative analysis of sulpiride, a significant antipsychotic drug, in human urine samples by the incorporation of excitation-emission matrix (EEM) fluorescence and second-order calibration methodologies based on the alternating fitting residue (AFR) and self-weighted alternating trilinear decomposition (SWATLD) algorithms. With the application of a second-order advantage, the proposed strategy could be utilized for a direct concentration determination of sulpiride with a simple pretreatment step, even in the presence of serious natural fluorescent interferences. The average recoveries of sulpiride in complex urine samples by using AFR and SWATLD with an estimated component number of three were 101.2 +/- 2.1 and 94.4 +/- 0.7%, respectively. Moreover, the accuracy of the two algorithms was also evaluated through elliptical joint confidence region (EJCR) tests as well as the figures of merit, such as sensitivity (SEN), selectivity (SEL) and limit of detection (LOD). The experimental results demonstrated that both algorithms, as promising quantitative alternatives, have been satisfactorily applied to the determination of sulpiride in human urine, but the performance of AFR was slightly better than that of SWATLD.

Cyclosporine A (CsA) affects the pharmacodynamics and pharmacokinetics of the atypical antipsychotic amisulpride probably via inhibition of P-glycoprotein (P-gp).

The importance of P-glycoprotein (P-gp) in the pharmacokinetics of amisulpride and the effects of a P-gp inhibitor cyclosporine A (CsA) was investigated both, in vitro and in vivo. In vitro and in vivo results indicated amisulpride as a substrate of P-gp. Amisulpride was not metabolized by rat liver microsomes. Open field behavior showed time dependent abolishment in locomotion by amisulpride (50 mg kg(-1)). Co-administration of CsA (50 mg kg(-1)) resulted in a higher and significantly longer antipsychotic effect (24 h after drug administration). Accordingly, the area under concentration-time curve in serum and brain was higher in CsA co-treated rats (13.5 vs. 29.8 micromol h l(-1) for serum and 2.16 vs 2.98 micromol h l(-1) for brain tissue) while renal clearance was not affected. These results pointed to a pharmacokinetic drug interaction between CsA and amisulpride most likely caused by inhibition of P-gp.

Improvement and validation of a liquid chromatographic method for the determination of levosulpiride in human serum and urine.

A rapid, selective and highly sensitive reversed-phase high-performance liquid chromatography (HPLC) method was developed for the determination of levosulpiride, 5-(aminosulfonyl)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2-methoxy benzamide, in human serum and urine. The method involved the extraction with a dichloromethane followed by back-extraction into 0.025 M sulfuric acid. HPLC analysis was carried out using reversed-phase isocratic elution with a Luna C(18)(2) 5 microm column, a mobile phase of acetonitrile-0.01 M potassium hydrogen phosphate (30:70, v/v, adjusted to pH 8.5 with triethylamine), and a fluorescence detector with excitation at 300 nm and emission at 365 nm. The chromatograms showed good resolution and sensitivity and no interference of human serum and urine. The calibration curves were linear over the concentration range 0.25-200 ng/ml for serum and 0.2-20 microg/ml for urine with correlation coefficients greater than 0.997. Intra- and inter-day assay precision and accuracy fulfilled the international requirements. The mean absolute recovery for human serum was 89.8+/-3.7%. The lower limits of quantitation in human serum and urine were 0.25 ng/ml and 0.2 microg/ml, respectively, which were sensitive enough for pharmacokinetic studies. Stability studies showed that levosulpiride in human serum and urine was stable during storage, or during the assay procedure. This method was successfully applied to the study of pharmacokinetics of levosulpiride in human volunteers following a single oral administration of levosulpiride (25 mg) tablet.

Determination of sulpiride by capillary electrophoresis with end-column electrogenerated chemiluminescence detection.

BACKGROUND: Capillary electrophoresis (CE) with tris(2,2'-bipyridyl)ruthenium(II) [Ru(bpy)3(2+)]-electrogenerated chemiluminescence (ECL) detection is a promising method for clinical analysis. In this study, a method combining CE with Ru(bpy)3(2+) ECL (CE-ECL) detection that can be applied to amine-containing clinical species was developed, and the performance of CE-ECL as a quantitative method for determination of sulpiride in human plasma or urine was evaluated. METHODS: Sulpiride was separated by capillary zone electrophoresis in uncoated fused-silica capillaries [50 cm x 25 microm (i.d.)] filled with phosphate buffer (pH 8.0) and a driving voltage of +15 kV, with end-column Ru(bpy)3(2+) ECL detection. A platinum disc electrode was used as working electrode. Sulpiride in human plasma or urine samples (100 microL) was extracted by a double-step liquid-liquid extraction procedure, dried under nitrogen at 35 degrees C in a water bath, and reconstituted with 100 microL of filtered water. The extraction solvent was ethyl acetate-dichloromethane (5:1 by volume). RESULTS: Under optimum conditions (pH 8.0 phosphate buffer, injection for 6 s at 10 kV, and +1.2 V as detection potential), separation of sulpiride was accomplished within 4 min. The calibration curve was linear over a concentration range of 0.05-25.0 micromol/L, and the limit of detection was 2.9 x 10(-8) mol/L for sulpiride. Intra- and interday CVs for ECL intensities were <6%. Extraction recoveries of sulpiride were 95.6-101% with CVs of 2.9-6.0%. The method was clinically validated for patient plasma and urine samples. CONCLUSIONS: CE combined with Ru(bpy)3(2+) ECL is reproducible, precise, selective, and enables the analysis of sulpiride in human plasma and urine. It thus is of value for rapid and efficient analysis of amine-containing analytes of clinical interest.

Adsorptive stripping voltammetric determination of the antidepressant drug sulpiride.

The electrochemical behaviour of the antidepressant drug sulpiride (SP) at a hanging mercury drop electrode (HMDE) is investigated. Linear sweep cathodic stripping voltammetry (LSCSV) was used to determine sulpiride in the presence of 0.01 M sodium acetate medium pH 10.5 and 25 +/- 1 degrees C. Different parameters such as, supporting electrolyte, pH, accumulation potential, scan rate, accumulation time and ionic strength, were tested to optimize the conditions for the determination of SP. The adsorbed form is reduced irreversibly. The linear concentration range is from 2 x 10(-9) to 5 x 10(-8) M SP. Experimentally, 2 x 10(-9) M (0.68 ppb) with accumulation time 60 s can be determined successfully. Furthermore, a theoretical detection limit of 2 x 10(-10) M (0.068 ppb) Sp was calculated. The interferences of some metal ions, ascorbic acid and some amino acids were studied. The method was applied to the analysis of tablets and spiked urine, with recoveries of 104 +/- 3 and 101 + 3, and the relative standard deviation of 3.3 and 3.4%, respectively.

Inhibitory effects of procainamide and probenecid on renal excretion of sultopride enantiomers in rats.

The effects of the coadministration of procainamide and probenecid on the pharmacokinetic behavior of sultopride, an antipsychotic agent, after intravenous administration were studied with rats. The areas under the concentration-time curve for and renal clearances of (+)-sultopride and (-)-sultopride, which exist as organic cations under physiological pH conditions, were significantly decreased (p < 0.01) by the coadministration of procainamide, an organic cation under physiological pH conditions. The renal clearance of (-)-sultopride was partially decreased (p < 0.05) by the coadministration of probenecid, an organic anion under physiological pH conditions. The results suggest that drug-drug interactions between organic cations and organic anions occur to a certain extent during the tubular secretion process in rats.

Disposition of enantiomers of sultopride in a human, rats and rabbits.

Pharmacokinetics of sultopride enantiomers was examined following a single dose in a human, rabbits and rats. Pharmacokinetic profiles were similar between (+)- and (-)-enantiomers of sultopride in human, whereas the serum concentrations of (-)-sultopride were slightly higher than those of (+)-sultopride after i.v. administration of 50 mg/kg of racemic sultopride to rats and rabbits.

Absolute bioavailability, rate of absorption, and dose proportionality of sulpiride in humans.

The pharmacokinetics of orally administered sulpiride was determined in a series of three studies. In the first study, 12 subjects received an oral solution (200 mg) and an iv dose (100 mg). The second study also included an iv dose, and examined the absorption of 200-, 300-, and 400-mg doses given as 50-mg capsules to six subjects. The third study compared the bioavailability of a 200-mg capsule dose with a 200-mg im dose in eight subjects. The concentration of sulpiride in plasma, red blood cells, and urine was measured by HPLC. The disposition of the drug was generally best described by a two-compartment pharmacokinetic model, with absorption appearing to occur by two sequential zero-order processes. The fraction of dose absorbed after oral administration was approximately 30% based on plasma and urine data. After the 200-mg dose, the mean elimination half-life was 7.0 h, and the mean residence time was 8.4 h. For each subject, total clearance, corrected for the fraction absorbed, and renal clearance were similar. The dose proportionality study demonstrated linear disposition kinetics.

Pharmacokinetics of sulpiride in humans after intravenous and intramuscular administrations.

The pharmacokinetics of sulpiride in plasma, red blood cells (RBC), and urine were investigated after administration of 100 mg by the iv route to 15 subjects and by the im route to 12 subjects. The concentrations of sulpiride in plasma, RBC, and urine were measured by HPLC. All the data were consistent with a two-compartment, open-body model. After iv administration, the mean +/- SD apparent elimination half-life of sulpiride was 6.47 +/- 1.00 h, and the mean +/- SD volume of distribution at steady state was 0.94 +/- 0.23 L/kg. Renal clearance (119.5 +/- 28.2 mL/min) was very close to total clearance (127.8 +/- 26.2 mL/min). In urine, the mean +/- SD recovery in form of the unchanged drug was 90.0 +/- 9.68% of the administered dose, and the excretion rate versus time showed an elimination half-life similar to that found in plasma. The values of all these parameters were very close to those obtained after im administration. The sulpiride partition coefficient between RBC and plasma did not show any significant change as a function of time and concentration, with a mean value +/- SD of 1.00 +/- 0.043, indicating that sulpiride is evenly distributed between RBC and plasma. The pharmacokinetic parameters determined from the plasma and the RBC data were similar.

Effects of food intake on the bioavailability of sulpiride from AEA film-coated tablet having a pH-dependent dissolution characteristic in normal or drug-induced achlorhydric subjects.

The effect of food intake on the bioavailability of sulpiride from a commercial film-coated tablet (100 mg/T) treated with polyvinylacetal diethylaminoacetate (AEA), which remains undissolved at pH above 4 approximately 5, were investigated in four healthy male subjects in the normal state or in a drug-induced achlorhydric state. The drug was administered as a single oral 100 mg dose of sulpiride under the fasting and nonfasting state using a crossover study design. Fifteen urine samples were collected over a 48 h period following sulpiride administration to determine sulpiride concentrations by HPLC. The bioavailability was estimated from the cumulative amount excreted unchanged in urine over 48 h (Du48). When AEA film-coated tablet was taken by subjects in the normal state, the bioavailability under the fasting state differed markedly among the four subjects due to differences in gastric acidity. The effect of food intake on the bioavailability also differed markedly among the individuals, being lower in high gastric acidity subject and higher in those with low gastric acidity subjects. When AEA film-coated tablet was taken by subjects in a simulated achlorhydric state, the bioavailability under the fasting state was very poor for all four subjects and did not show inter-subject variation. With food intake, the bioavailability increased 6-fold, probably due to the more vigorous movement of the formulation in the gastrointestinal tract, since both the basal and the meal-stimulated gastric acid secretion were markedly inhibited in the simulated achlorhydric state.

A double-peak phenomenon in the pharmacokinetics of veralipride after oral administration: a double-site model for drug absorption.

Equal doses of veralipride have been given to 12 healthy volunteers by three different administrations--intravenous infusion, oral solution, and oral capsules--in a randomized cross-over design. After the intake of the solution, but not after infusion or capsules, two maximum plasma concentrations have been observed and interpreted, according to a double-site model for drug absorption.

Biotransformation of sultopride in man and several animal species.

The biotransformation of sultopride has been investigated in rat, rabbit, dog and man. In man sultopride was metabolically stable, and about 90% of an oral dose was excreted in urine unchanged and 4% as oxo-sultopride. Rat, rabbit and dog metabolized sultopride more extensively and excreted less than 40% of an oral dose of 14C-sultopride in urine. Four similar metabolites were excreted by the three animal species but the relative portions differed. The major radioactive component in rat urine was O-desmethyl sultopride, whereas oxo-sultopride and O-desmethyl sultopride were the major urinary metabolites in rabbit. Dog formed N-desethyl sultopride and oxo-sultopride as major urinary metabolites. The male rat excreted smaller amounts of unchanged sultopride in urine than did the female rat. The unchanged sultopride excreted in rat urine was increased slightly by repeated administration.

[Determination of sulpiride and sultopride by high-performance liquid chromatography for pharmacokinetic studies]. / Dosage du sulpiride et du sultopride par chromatographie liquide à haute performance en vue de leur étude pharmacocinetique.

A high-performance liquid chromatographic method with UV detection (226 nm) for the analysis of sulpiride and sultopride in body fluids has been developed. Plasma, red blood cell (RBC) and urine samples were extracted by chloroform at pH 10. Internal standards were a new substituted benzamide (N-[(ethyl-1-pyrrolidinyl-2)methyl] methoxy-2-ethylsulphonyl-5-benzamide, DAN) for the sulpiride assay and sulpiride for the sultopride assay. The detection limit in plasma and RBC was 10 ng/ml for sulpiride and 15 ng/ml for sultopride. The proposed techniques were selective, reliable and sensitive enough to be used for pharmacokinetic studies and drug monitoring. Some plasma and RBC data from pharmacokinetic studies in healthy volunteers (sulpiride) or patients (sultopride) are presented. Half-lives determined from either plasma or RBC concentrations were similar (7 h for sulpiride and 5 h for sultopride).

Quantitative analysis of veralipride in plasma and urine by gas chromatography-mass spectrometry and gas chromatography with flame-ionization detection.

A highly sensitive and selective quantitative assay for unchanged veralipride has been developed. The compound is extracted from alkalized samples (plasma or urine) with dichloromethane and converted to its trimethylated derivative by reaction with trimethylanilinium hydroxide. The reaction mixture is then chromatographed on a 3% OV-1 column. Trimethylated derivatives of plasma samples were assayed by selected-ion monitoring in the chemical-ionization mode and quantified by comparing the intensity of the quasi-molecular ion m/z 426 (M + H) with the intensity of the corresponding ion from trideuterated internal standard, m/z 429 (M + H). Flame-ionization detection was used for the assay of urine samples. The peak height ratio of trimethylated veralipride over trimethylated sulpiride, the internal standard, was used for quantitation of urine samples. A relative standard deviation of less than 10% was found when quantifying 10 ng/ml veralipride in plasma or 1 microgram/ml in urine.

Primary dose-dependent pharmacokinetic study of veralipride.

A dose-dependent pharmacokinetic study of veralipride (a new post-menopausal "hot flushes" regulator) was developed in humans after oral solution administration (100, 150, 200, and 250 mg). In most cases, two maxima of plasma drug concentrations occurred, probably due to a double intestinal site of absorption. From model independent pharmacokinetic parameters, it can be concluded that a linearity in the tested range doses exists.