Hyphenation of field-amplified sample injection and transient isotachophoresis in CE for the determination of sotalol and metoprolol in human urine samples.

A sensitive approach of capillary electrophoresis coupled with field-amplified sample injection and transient isotachophoresis was developed for the simultaneous determination of two ß-blockers: sotalol and metoprolol. In this dual focusing technique, the samples were prepared via only dissolution in ultrapure water and then injected electrokinetically. Phosphate acted as both the background electrolyte and the leading electrolyte. Its optimized concentration was 80 mM. A total of 25 mM of glycine was used as the terminating electrolyte. Under optimum conditions, good separation of sotalol and metoprolol was achieved within 10 min. In comparison with the conventional method, the sensitivity enhancement factors were up to 1031 and 919 for sotalol and metoprolol, respectively. The proposed method was employed in the determination of sotalol and metoprolol in spiked human urine samples. The limits of detection and limits of quantitation obtained via ultraviolet detection were 5 and 12 ng/mL, respectively, for sotalol, and 10 and 25 ng/mL, respectively, for metoprolol. The intraday repeatability values were lower than 2.7 and 1.7% for peak area and migration time, respectively. The assay is a simple and efficient strategy with potential for application in clinical and biochemical laboratories for monitoring sotalol and metoprolol.

Characterization of carbon nanotubes decorated with NiFe2O4 magnetic nanoparticles as a novel electrochemical sensor: application for highly selective determination of sotalol using voltammetry.

A magnetic nano-composite of multiwall carbon nanotube, decorated with NiFe2O4 nanoparticles, was synthesized with citrate sol-gel method. The multiwall carbon nanotubes decorated with NiFe2O4 nanoparticles (NiFe2O4-MWCNTs) were characterized with different methods such as Fourier transform infrared spectroscopy (FT-IR), transmission electron microscopy (TEM), atomic force microscopy (AFM), vibrating sample magnetometer (VSM), cyclic voltammetry (CV), and electrochemical impedance spectroscopy (EIS). The new nano-composite acts as a suitable electrocatalyst for the oxidation of sotalol at a potential of 500 mV at the surface of the modified electrode. Linear sweep voltammetry exhibited two wide linear dynamic ranges of 0.5-1000 µmol L(-1) sotalol with a detection limit of 0.09 µmol L(-1). The modified electrode was used as a novel electrochemical sensor for the determination of sotalol in real samples such as pharmaceutical, patient and safe human urine.

Extraction and preconcentration of beta-blockers in human urine for analysis with high performance liquid chromatography by means of carrier-mediated liquid phase microextraction.

A novel method was developed for the analysis of four beta-blockers, namely sotalol, carteolol, bisoprolol, and propranolol, in human urine by coupling carrier-mediated liquid phase microextraction (CM-LPME) to high performance liquid chromatography (HPLC). By adding an appropriate carrier in organic phase, simultaneous extraction and enrichment of hydrophilic (sotalol, carteolol, and bisoprolol) and hydrophobic (propranolol) drugs were achieved. High enrichment factors were obtained by optimizing the compositions of the organic phase, the acceptor solution, the donor solution, the stirring rate, and the extraction time. The linear ranges were from 0.05 to 10.0 mg L(-1) for sotalol and carteolol, and from 0.05 to 8.0 mg L(-1) for bisoprolol and propranolol. The limits of detection (S/N=3) were 0.01 mg L(-1) for sotalol, carteolol, and bisoprolol, and 0.005 mg L(-1) for propranolol. The relative standard deviations were lower than 6%. The developed method exhibited high analyte preconcentration and excellent sample clean-up effects with little solvent consumption and was found to be sensitive and suitable for simultaneous determination of the above four drugs spiked in human urine. Furthermore, the successful analysis of propranolol in real urine specimens revealed that the determination of beta-blockers in human urine is feasible using the present method.

Simultaneous RP-HPLC determination of sotalol, metoprolol, alpha-hydroxymetoprolol, paracetamol and its glucuronide and sulfate metabolites in human urine.

The HPLC method for the determination of sotalol (SOT), metoprolol (MET) and alpha-hydroxymetoprolol metabolite (MET-H), paracetamol (PAR), paracetamol glucuronide (PAR-G) and paracetamol sulfate (PAR-S) in human urine is described. Analyses were carried out on a reversed-phase LiChroCART Purospher C18e column (125 mm x 3 mm, 5 microm particles) (Merck) with gradient elution as well as spectrophotometric and fluorometric detection. Good resolution of the analyzed substances was obtained within a time range of no longer than 15 min. The linearity ranges of the callibration curves in human urine (as matrix) were: 3.25-45 microg ml(-1) (SOT), 0.75-40 microg ml(-1) (MET), 0.6-40 microg ml(-1) (MET-H), 4.6-60 microg ml(-1) (PAR-G), 4.95-50 microg ml(-1) (PAR-S), 1.95-45 microg ml(-1) (PAR). An application to human urine samples was performed.

Influence of cimetidine coadministration on the pharmacokinetics of sotalol enantiomers in an anaesthetized rat model: evidence supporting active renal excretion of sotalol.

Sotalol (STL) is an amphoteric, chiral beta-adrenergic blocking drug useful in the treatment of both hypertension and ventricular arrhythmias. In the human and rat, STL enantiomers are predominantly cleared from the body by the kidney as intact drug. The renal clearance (Clr) of STL enantiomers substantially exceeds the glomerular filtration rate (GFR) in the human and rat. In this report, the hypothesis that STL enantiomers are excreted by an active renal transport system was investigated in the rat by coadministering racemic STL (10 mg kg-1) with cimetidine, an inhibitor of renal tubular secretion of organic cations. To compare the effects of short-term and sustained cimetidine exposure on STL enantiomer disposition, cimetidine was administered either as a single bolus (30 mg kg-1, n = 7) immediately prior to the STL dose, or as a 30 mg kg-1 bolus plus a 50 mg kg-1 infusion over the 6 h study period (n = 7). Blood and urine samples were collected over 6 h, during which time anaesthesia was maintained via intraperitoneal administration of pentobarbital. Cimetidine bolus and cimetidine infusion reduced STL enantiomer Clr by 43 and 59%, respectively, compared with respective saline controls. Significant stereoselectivity was observed in the cimetidine infusion group: systemic clearance, Clr (R > S), and AUC (S > R), although the magnitude of stereoselectivity was less than 5%. This study supports the hypothesis that STL enantiomers are predominantly cleared from the rat via a renal cationic transport mechanism and that this system can be competitively inhibited by the presence of cimetidine.

Enantioselective determination of sotalol enantiomers in biological fluids using high-performance liquid chromatography.

A simple and sensitive high-performance liquid chromatographic (HPLC) method for the determination of (+)-(S)-sotalol and (-)-(R)-sotalol in biological fluids was established. Following extraction with isopropyl alcohol from biological samples on a Sep-Pak C18 cartridge, the eluent was derivatized with 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl isothiocyanate (GITC). The diastereoisomeric derivates were resolved by HPLC with UV detection at 225 nm. Calibration was linear from 0.022 to 4.41 micrograms/ml in human plasma and from 0.22 to 88.2 micrograms/ml in human urine for both (+)-(S)- and (-)-(R)-sotalol. The lower limit of determination was 0.022 microgram/ml for plasma and 0.22 microgram/ml for urine. The within-day and day-to-day coefficients of variation were less than 7.5% for each enantiomer at 0.09 and 1.8 microgram/ml in plasma and at 0.44 and 4.4 micrograms/ml in urine. The method is also applicable to other biological specimens such as rat, mouse and rabbit plasma.

Stereospecific evaluation of sotalol pharmacokinetics in a rat model: evidence suggesting an enantiomeric interaction.

Sotalol (STL) is a chiral beta-adrenergic blocking drug, which is useful clinically as the racemate in treating hypertension, and is also useful as a class III antiarrhythmic when administered as the pure S-enantiomer. Utilizing a stereospecific high-performance liquid chromatographic (HPLC) assay, the enantiomeric disposition of STL is reported after administration of racemate and both pure enantiomers to a rat model. After administration of the racemate, enantiomers of STL had similar plasma concentration-time profiles. Following administration of the pure S-enantiomer of STL, however, systemic clearance was significantly reduced; R-STL disposition after pure enantiomer administration was not significantly altered. Changes in systemic clearance of S-STL after either racemate or enantiomer dosing were explained by corresponding changes in renal clearance. Renal clearance values of S-STL were significantly reduced from 33.7 +/- 6.0 to 28.9 +/- 5.6 ml min-1 kg-1 for administration as racemate and pure enantiomer, respectively. As clearance of STL approximates reported values of renal blood flow, renal perfusion changes caused by the beta-blocking effects of R-STL may explain changes in S-STL disposition. It is suggested that dosing of STL as either racemate or pure enantiomer, depending on the clinical indication for use, may result in significantly altered enantiomer disposition.

Stereoselective disposition of (+/-)-sotalol at steady-state conditions.

The objective of this study was to assess, under steady-state conditions, the stereoselective disposition of (+/-)-sotalol in man. In all patients studied (n = 7) values of oral clearance (137 +/- 51 ml min-1), renal clearance (96 +/- 42 ml min-1) and nonrenal clearance (41 +/- 25 ml min-1) of (-)-sotalol were greater than those for (+)-sotalol (123 +/- 45 ml min-1, 89 +/- 39 ml min-1 and 34 +/- 23 ml min-1, respectively; P < 0.05, Student's paired t-test). Binding to plasma proteins was greater for (+)-sotalol (38 +/- 9% vs 35 +/- 9% for the (-)-enantiomer; P < 0.05) such that unbound oral clearance (+)/(-) ratio (0.95 +/- 0.06) and unbound renal clearance (+)/(-) ratio (0.97 +/- 0.06) were not stereoselective. In contrast, estimated unbound nonrenal clearance, which represents approximately 25% of the total unbound clearance of the drug, was greater for the (-)-enantiomer (64 +/- 42 ml min-1) compared with (+)-sotalol (57 +/- 42 ml min-1; P < 0.05). The difference in the pharmacokinetics of sotalol enantiomers is mainly related to stereoselectivity in plasma protein binding.

Thermospray liquid chromatography/mass spectrometry of polar beta-blocking drugs: preliminary results.

The use of thermospray liquid chromatography for the screening of polar beta-blocking drugs is evaluated. The influence of instrumental parameters on the fragmentation pattern of labetalol, acebutolol, diacetolol, sotalol and atenolol is described. A short biomedical application is presented.

Liquid chromatographic determination of sotalol in plasma and urine employing solid-phase extraction and fluorescence detection.

A liquid chromatographic method using a solid-phase extraction procedure for the quantification of sotalol in plasma and urine is described. Sotalol is eluted from an extraction column with ethyl acetate-acetonitrile (1:2) and, after separation by reversed-phase high-performance liquid chromatography on a mu Bondapak C18 column, is quantified by fluorescence detection at excitation and emission wavelengths of 240 and 310 nm, respectively. The method has been demonstrated to be linear over the concentration ranges 10-6000 ng/ml in plasma and 0.5-100 micrograms/ml in urine. Mean inter-assay accuracy of the method for plasma ranged from 93 to 100% and for urine from 102 to 114%; precision ranged from 0.5 to 1.6% for plasma over a concentration range of 200-4000 ng/ml and for urine from 0.7 to 2.0% at concentrations of 2-50 micrograms/ml. Mass spectrometry confirmed the presence of sotalol in isolated chromatographic fractions of plasma and urine extracts from subjects given sotalol orally.

High-performance liquid chromatographic determination of sotalol in biological fluids.

A sensitive, selective and reproducible reversed-phase high-performance liquid chromatographic method is described for the quantification of sotalol in human serum and urine. Sotalol and the internal standard, atenolol, were extracted from alkalinized serum and urine (pH 9.0) into 1-butanol--chloroform (20:60, v/v). The organic phase was evaporated, and to the residue was added 0.1 M sulphuric acid (serum analysis) or mobile phase (urine analysis). The mobile phase consisted of 0.01 M phosphate buffer (pH 3.2) and acetonitrile (20:80, v/v) containing 3 mM n-octylsodium sulphate. The flow-rate was 1.5 ml/min. The retention times of atenolol and sotalol were 7 and 10 min, respectively. Ultraviolet detection at 226 nm made it possible to achieve a detection limit of 0.03 mumol/l.

Effect of oral charcoal and urine pH on sotalol pharmacokinetics.

The effects of orally given activated charcoal, sodium bicarbonate and ammonium chloride on the pharmacokinetics of sotalol were studied in 7 volunteers in a randomized, cross-over study. Serum and urine concentrations of sotalol were determined by HPLC up to 72 h. Activated charcoal, 50 g, given within 5 min of sotalol hydrochloride (160 mg), reduced its absorption by 99%. When given in repeated doses from 6 h on, 50 g followed by 12.5 g at 6 h intervals, charcoal shortened the half-life after sotalol in serum from 9.4 +/- 0.4 h to 7.6 +/- 0.3 h and in urine from 9.4 +/- 0.4 h to 7.3 +/- 0.3 h (p less than 0.01). The excretion of unchanged sotalol into urine was 65% of the dose during the control phase but neither acidification nor alkalinization of urine for 3 days did increase its urinary excretion. Thus, activated charcoal seems to be effective in prevention of the absorption of sotalol when ingested without delay. Given in repeated oral doses charcoal moderately increases the rate of sotalol elimination, probably by interrupting its enterohepatic or enteroenteric circulation.

Pharmacokinetics of sotalol during pregnancy.

Sotalol, a beta-adrenoceptor blocking drug, was administered to 6 healthy pregnant volunteers between 32-36 weeks gestation and when at least 6 weeks post-partum. On both occasions, each volunteer was given sotalol 100 mg intravenously and 400 mg orally in randomised order with at least a 1 week washout period between. Plasma samples were analysed for sotalol using a fluorometric method and the pharmacokinetic profiles investigated. The systemic clearance of sotalol was significantly greater in the antenatal period (2.4 +/- 0.3 ml/min/kg) than in the post-natal phase (1.5 +/- 0.1 ml/min/kg). The apparent volume of distribution was similar in the two periods: the elimination half-life was 6.6 +/- 0.6 h ante-natally and 9.3 +/- 0.7 h post-natally after intravenous drug but the trend for faster elimination was not significant. The elimination half-life after oral administration (about 10 h) and bioavailability (about 90%) were not altered significantly by pregnancy. It is suggested that the more rapid clearance of sotalol in pregnancy may be due to increases in renal plasma flow and glomerular filtration rate.

Fluorometric high-performance liquid chromatographic determination of sotalol in biological fluids.

A high-performance liquid chromatographic (HPLC) method for sotalol in biological fluids is presented. Sample preparation involves a simple acid-base double-extraction procedure, and analysis is carried out on a reversed-phase chromatographic system using a muBondapak C18 column. Procainamide was used as the internal standard. As little as 20 ng of sotalol/ml can be detected with good precision by a fluorometric detector. HPLC, which allows more rapid analysis of plasma sotalol levels than does GLC, appears suitable for pharmacokinetic studies as well as for therapeutic drug monitoring.