Propofol In Plasma Research Articles

Fast Determination of Propofol in Human Plasma Using C18-Functionalized Magnetic Nanomaterials Followed by Supercritical Fluid Chromatography.

Novel C18-functionalized magnetic nanomaterials; i.e., C18@poly-styrene-divinylbenzene-glycidyl methacrylate-Fe3O4 (C18@PS-DVB-GMA-Fe3O4) have been synthesized by using N, N-dimethyloctadecylamine as modifying agent, which could be beneficial to remove the blood phospholipids. The C18@PS-DVB-GMA-Fe3O4 nanoparticles have been used and evaluated in the Quick, Easy, Cheap, Effective, Rugged and Safe (QuEChERS) procedure for human plasma prior to the analysis of propofol by supercritical fluid chromatography (SFC). In the QuEChERS procedure, human plasma samples are directly mixed with extraction solvent and C18@PS-DVB-GMA-Fe3O4 nanoparticles, and the extraction and cleanup procedures have been accomplished simultaneously. The SFC separation was performed with a C18 column (Thermo Scientific™ Acclaim™ 120, 250 × 4. 6mm, 5μm) within 5min, using thymol as the internal standard. Supercritical carbon dioxide was used as the mobile phase with methanol as the cosolvent at the flow rate of 1.0mL/min. The column temperature was 38°C, and detection wavelength was 275nm. A good linearity was obtained among the propofol concentration range of 0.5-10mg/L (R2 = 0.9997) with the limit of detection of 0.17mg/L. Recoveries were in the range of 76.5-91.9%, with RSD less than 7.9%. These results suggested that method is convenient, rapid with high accuracy and little matrix effect, and suitable for rapid determination of propofol plasma concentration.

Propofol does not alter the protein binding and unbound concentration of lidocaine at clinically targeted plasma concentrations in vitro – A short communication

BackgroundIntravenous lidocaine is increasingly used as an analgesic adjunct during general anaesthesia. Lidocaine is highly protein-bound and changes to binding can alter drug efficacy or toxicity. We aimed to measure the effect of various propofol and lidocaine plasma concentration combinations on the protein binding and concentration of lidocaine in vitro. MethodsKnown targeted concentrations of propofol and lidocaine were added to drug-free human plasma in vitro. Samples were prepared and analysed in various clinically relevant concentration combinations; propofol at 0, 2, 4 and 6 µg/mL, and lidocaine at 1, 3 and 5 µg/mL. The total and unbound concentrations of lidocaine were measured by ultra-high performance liquid chromatography-mass spectrometry and percentage protein binding was determined. Data were presented as mean and standard deviation (SD) and differences between groups analysed. ResultsThe overall mean protein binding of lidocaine was 68.8% (SD 5.5, range 57.5–80.9%). Beta regression analysis revealed no statistically significant difference in lidocaine percentage binding across a range of propofol and lidocaine concentration combinations. ConclusionPropofol did not alter the unbound and free pharmacologically active proportion of lidocaine at different clinically targeted concentrations of propofol and lidocaine in plasma in vitro. The percentage of plasma protein binding of lidocaine in this study was consistent with previously published results.

U-shape functionalized optical fibre sensors for measurement of anaesthetic propofol

Propofol is used widely for intravenous anaesthesia during surgery and sedation in critical care. There is no method currently to assay the concentration of propofol in plasma in real time. The ability to do so would significantly improve patient safety. A novel approach to propofol assay consisting of Beta-Cyclodextrin (β−CD) assisted propofol-imprinting onto TiO2 films deposited on U-shaped optical fibres was used for the measurement of propofol in aqueous solutions. The sensing mechanism is based on the measurement of the refractive index change induced by the removing and binding of the propofol from and to the β−CD/propofol complex embedded onto TiO2 films, respectively. Complexation between host (β−CD) and guest (propofol) was confirmed by nuclear magnetic resonance (NMR) spectroscopy, UV-Vis spectroscopy, and by Attenuated Total Reflectance- Fourier-transform infrared spectroscopy (FTIR). The developed sensors presented Langmuir adsorption in the mM range and the lowest concentration detected was 0.69 μM= 0.12 μg/ml. The approach can be replicated for other compounds in other biomedical applications such as vitamins, hormones, or drugs.

Comparison of predicted and real propofol and remifentanil concentrations in plasma and brain tissue during target‐controlled infusion: a reply

Comparison of predicted and real propofol and remifentanil concentrations in plasma and brain tissue during target‐controlled infusion: a reply

Determination of propofol in human plasma with C18 pipette-tip based solid-phase extraction followed by liquid chromatography atmospheric-pressure chemical ionization tandem mass spectrometry analysis

Propofol is a widely used intravenous anesthetic for sedation during the surgery and worldwide propofol abuse has been frequently reported also. As an essential procedure for sample pretreatment, solid-phase extraction (SPE) is generally time-consuming and labor-intensive, which hindered the further improvement in the analysis of propofol from biological fluids. In this study, a rapid C18 pipette-tip based SPE method was developed to pretreat human plasma samples directly, bypassing the need for protein precipitation. The experiment conditions were optimized for the best extraction recovery (23.6 ± 4.1 %). After pretreatment, the plasma propofol was determined with liquid chromatography atmospheric-pressure chemical ionization-tandem mass spectrometry (LC-APCI-MS/MS) using propofol-d17 as the internal standard. The quantification method showed good linearity in the range of 0.005–5 μg mL−1 (r2 = 0.9992). The sensitivity, specificity, accuracy (90.0–113.3 %), precision (2.0–8.9 %), and stability (95.6–102.1 %) were satisfied for bioanalytical analysis. Finally, the concentrations of propofol in the plasma of a patient under anesthesia were determined with the proposed method and compared with the theoretical concentrations calculated with a population pharmacokinetics (popPK) model. In general, this work provided a rapid and straightforward method for the study of propofol in pharmacokinetics and forensic science.

A simplified and sensitive LC-APCI-MS/MS method for the quantification of propofol: Application to a bioequivalence study in healthy Chinese subjects

Propofol has become the preferred anesthetic in recent years due to its desirable pharmacologic properties. However, propofol possesses a very narrow therapeutic window between the favorable clinical effect and potentially lethal toxicity, therefore, a rapid, simplified, and sensitive liquid chromatography-atmospheric pressure chemical ionization tandem mass spectrometry (LC-APCI-MS/MS) method is presented in this study for the quantification of propofol in human plasma using the isotope-labeled internal standard (IS) of propofol-d17, and then applied in a bioequivalence study. Sample preparation was accomplished through simple one-step precipitation of plasma protein with acetonitrile. Chromatographic separation was acquired on an ACE Excel 3 Super C18 column (2.1 × 50 mm, 3µm) using gradient elution at a flow rate of 0.5mL/min. The MS detection was achieved in the negative ion APCI by multiple reaction monitoring (MRM) mode using the transitions of m/z 177.2 → 161.0 for propofol and m/z 194.2 → 174.2 for IS, respectively. 30 healthy Chinese subjects were enrolled in the open-label, randomized, two-period, two-sequence, cross-over bioequivalence study after single-dose intravenous administration of propofol medium-chain triglyceride and long-chain triglyceride (MCT/LCT). The current method was precise and accurate at a linearity range of 4.00-1,000ng/mL without severe interference from the plasma matrix. The inter- and intra-batch precision (2.3 to 15.8%) and accuracy (-4.4 to 3.0%), IS-normalized matrix effect (coefficient of variation ≤4.6%), extraction recovery (107.1-117.1%), stability (coefficient of variation ≤8.0%), and dilution integrity were all within the acceptable range. The 90% confidence intervals (CIs) of the ratios of the geometric means (test/reference) were 86.44-104.88% for Cmax, 96.30-104.52% for AUC0-t, and 96.56-105.05% for AUC0-∞, which were all within the predefined bioequivalence range of 80-125%. Besides, both propofol MCT/LCT preparations were well tolerated in healthy Chinese subjects, and there were no serious adverse events during the study. The method is more simplified and sensitive than the previously reported modes of propofol detection. The two propofol MCT/LCT preparations were considered to be bioequivalent.

Sensitive determination of midazolam and propofol in human plasma by GC–MS/MS

A sensitive method was developed for the simultaneous determination of midazolam and propofol in human plasma samples via modified quick, easy, cheap, effective, rugged, and safe (QuEChERS) extraction for their analysis by gas chromatography–tandem mass spectrometry (GC–MS/MS). Detailed optimization and validation experiments were conducted; plasma quality control samples spiked with two drugs and two internal standards (ISs) were extracted using the QuEChERS technique and determined by GC–MS/MS. The present method was applied to the measurements in an actual clinical case. The regression equations for midazolam and propofol in plasma displayed good linearity (r > 0.9978) from 10 to 1000 ng/mL with a limit of quantification of 10 ng/mL. The intra- and interday precisions for both drugs were not greater than 8.6%. The accuracies of quantitation ranged from 98 to 110%. The extraction efficiencies of midazolam and propofol for plasma were 93 to 117%. The method was successfully applied to the analyses of plasma midazolam and propofol concentrations in a brain-injured patient subjected to hypothermia, which validated the present methodology. In this study, the authors have successfully established the detailed procedure for GC–MS/MS analysis of midazolam and propofol in human plasma. The sensitivity and specificity of the present method for the drugs were almost comparable to those by the standard liquid chromatography–tandem mass spectrometry. To their knowledge, this is the first report for analysis of midazolam/propofol by GC–MS/MS.

Design and validation of an automated solid phase extraction liquid chromatography coupled mass spectrometry method for the quantification of propofol in plasma

Propofol concentration in human plasma can be quantified by liquid chromatography coupled mass spectrometry. Sample preparation usually requires solid phase extraction to remove matrix components and enrich the analyte. To facilitate user-independent measurements and speed extraction, we developed and validated a fully automated high throughput in-line sample preparation system with direct injection into liquid chromatography coupled mass spectrometry. We assessed linearity of each method over the clinically relevant concentration range from 0.5μg/mL to 8μg/mL plasma concentration. R2 values were 0.99 for the automated process and 0.98 for manual sample preparation. The limit of detection was 6ng/mL and the lower limit of quantification was 18ng/mL for the automated method; for the manual process, the limit of detection was 1.58ng/mL and the lower limit of quantification was 4.79ng/mL. Intra-day precision for low, medium and high concentration range of the automated method was validated 4.14%, 9.68% and 3.04% relative standard deviation and 0.29%, 0.12% and 0.52% for the manual process. Carry over was 0.4% with the automated method, whereas there was no carry over with the manual method. Stability of plasma samples was tested with the manual method at concentrations of 1, 4, and 6μg/mL propofol and found to be stable over 150days at −20°C. The manual sample preparation method has successfully been transferred to a fully automated process with appropriate sensitivity and precision but the automatization failed with regard to trueness and working time due to lengthy sample preparation runtime. Therefore it is not suitable for daily use in a hospital laboratory e.g. for brain death diagnosis in the intensive care unit.

A membrane separator interface for mass-spectrometric analysis of desflurane, propofol, and fentanyl in blood plasma and cerebrospinal fluid

An easy-to-operate mass-spectrometric membrane separator interface, which is intended for measuring the concentrations of anesthetic preparations in biological fluids (blood plasma and cerebrospinal fluid), is described. Biological fluids are sampled during balanced inhalation (desflurane, fentanyl) anesthesia and total intravenous (desflurane, propofol) anesthesia. In the design of the mass-spectrometer interface, a hydrophobic membrane that separates anesthetic preparations from biological fluids is used: inhalation anesthetic desflurane, hypnotic propofol, and analgetic fentanyl. It was revealed that the membrane does not degrade during multiple (up to 30 cycles) measurements. The possibility of using the interface for measuring the absolute concentrations of desflurane and propofol in blood plasma and cerebrospinal fluid when studying the properties and degree of degradation of the blood–brain barrier in the in situ mode.

Selective and Accurate Determination Method of Propofol in Human Plasma by Mixed-Mode Cation Exchange Cartridge and GC-MS.

A gas chromatography-mass spectrometry (GC-MS) method for the determination of propofol in human plasma has been developed and validated. Propofol was extracted from human plasma by using mixed-mode cation exchange/reversed-phase (MCX) cartridges. As propofol easily volatilizes during concentration, 100% methanol was injected directly into GC-MS to elute propofol. Despite avoiding concentration process of the eluted solution, lower limit of quantization (LLOQ) of propofol was 25 ng/mL. The validated method exhibited good linearity (R 2 = 0.9989) with accuracy and precision −5.8%~11.7% and 3.7%~11.6%, respectively. The other validation parameters, recovery and matrix effect, ranged from 96.6% to 99.4% and 95.3% to 101.4%, respectively. Propofol standard was quantified to evaluate possible loss due to the concentration processes, nitrogen gas and centrifugal vacuum. These two concentration processes resulted in notable decrease in the quantity of propofol, signifying avoiding any concentration processes during propofol quantification. Also, to confirm suitability of the developed method, authentic human plasma samples were analyzed. The selective assay method using MCX cartridge and GC-MS facilitated quantification of propofol in plasma sample accurately by preventing any losses due to the concentration processes.

Quantification of remifentanil and propofol in human plasma: a LC-MS/MS assay validated according to the EMA guideline.

Remifentanil and propofol are often used in combination for general anesthesia. We developed a method using LC-MS for their simultaneous measurement in human plasma. Methodology & results: After addition of remifentanil-(13)C6 and propofol-d18 (IS), 500 µl of plasma were extracted with ethylacetate/hexane. Analysis conditions included gradient elution (water/acetonitrile), electrospray ionization and detection with a triple quadripole mass spectrometer. Remifentanil and propofol were ionized in the positive and negative mode, respectively. The method was validated according to the European Medicines Agency guideline for the validation of bioanalytical methods, then successfully applied to clinical samples from three patients who had undergone liver transplantation. This method is suitable for the simultaneous quantification of remifentanil and propofol in clinical studies.

Efficacy of high performance liquid chromatography for simultaneous determination of propofol and remifentanil concentrations in human plasma

Objective To evaluate the efficacy of high performance liquid chromatography(HPLC)for simultaneous determination of propofol and remifentanil concentrations in human plasma. Methods Methods Eighteen healthy volunteers of both sexes, aged 18-45 yr, weighing 52-81 kg, were enrolled in the study.Venous blood samples were collected, and the concentrations of propofol and remifentanil in human plasma were detected simultaneously by HPLC.The internal standard was thymol.Potassium dihydrogen phosphate 0.1 mol/L was added to the plasma and then the plasma samples were extracted with extract liquor(ethyl acetate∶hexane=4∶1, V/V). The analytical column was ZORBAX Eclipse XDB-C18(4.6 mm×250 mm, 5 μm). The mobile phase was methano∶0.02 mol/L NaH2PO4∶acetonitrile, the flow rate was 1.0 ml/min, the detection wavelength was 210 nm within 1-7 min, and 266 nm within 7-16 min, and the sample size was 20 μl.Linear regression analysis was performed by using the least-squares method.The specimens of the blood with the final concentration of remifentanil 1.00, 5.00 and 20.00 ng/ml and propofol 0.50, 2.00 and 10.00 μg/ml were obtained to determine the recovery, precision and stability. Results Linear regression equation of remifentanil was C=12.853 5Ai/As+ 0.084 8(R2=0.999 4), and this system showed a good linear relationship with the concentration of remifentanil ranged 0.5-40.0 ng/ml.Linear regression equation of propofol was C=8.554 3Ai/As+ 0.029 1(R2=0.998 6), and this system showed a good linear relationship with the concentration of propofol ranged 0.2-20.0 μg/ml.For both propofol and remifentanil concentrations, the relative recovery was within the range of 85%-115%, the absolute recovery was larger than 75%, and the relative standard deviation of intra- and inter-day precision and stability was less than 5%.The method was proved to meet the requirements of biological sample analysis. Conclusion For HPLC method established in this trial, the determination is sensitive, reproducible, rapid and simple, and it can be used for simultaneous determination of propofol and remifentanil concentrations in human plasma and for clinical pharmacokinetic research. Key words: Chromatography, high pressure liquid; Propofol; Piperidines; Plasma concentration

Validation of an LC-MS/MS Method for the Determination of Propofol, Midazolam, and Carbamazepine in Rat Plasma: Application to Monitor Their Concentrations Following Co-administration.

Propofol (PRO) is a hypnotic used to induce and maintain general anesthesia. A risk of drug-drug interactions exists in cases of clinical co-administration of PRO and midazolam (MDZ) or carbamazepine (CBZ). Therefore a sensitive and rapid assay is needed to monitor these drugs. In this study, a sensitive and selective liquid chromatography-tandem mass spectrometry technique was developed for simultaneous determination of PRO, MDZ, and CBZ in plasma. Simultaneous selected reaction monitoring in the positive and negative ionization modes was used for mass detection. Analytes were isolated from plasma samples by a simple, economic, and rapid solid-phase extraction method. Chromatographic separations were achieved using a Chromolith Performance RP-18e analytical column (100×4.6 mm i.d.) with a mixture of acetonitrile-ammonium acetate buffer (10 mM, pH 3.5) (90 : 10, v/v) as the mobile phase. The method was fully validated for PRO, MDZ, and CBZ over concentrations ranging at 1-100, 2-100, and 7-1000 ng/mL, respectively, with acceptable validation parameters. Furthermore, the method was applied to monitor PRO and MDZ or CBZ following co-administration in rats.

High-performance liquid chromatographic determination of propofol in human plasma: comparison of different heteroscedastic calibration curve models.

The aim of this study was to select the best calibration model for determination of propofol plasma concentration by high-performance liquid chromatography method. Determination of propofol in plasma after deproteinization with acetonitrile containing thymol (as internal standard) was carried out on a C18 column with a mixture of acetonitrile and trifluoroacetic acid 0.1% (60:40) as mobile phase which delivered at the flow rate of 1.2 mL/minute . Fluorescence detection was done at the excitation and emission wavelengths of 276 and 310 nm, respectively. After fitting different equations to the calibration data using weighted regression, the adequacy of models were assessed by lack-of-fit test, significance of all model parameters, adjusted coefficient of determination (R(2) adjusted) and by measuring the predictive performance with median relative prediction error and median absolute relative prediction error of the validation data set. The best model was a linear equation without intercept with median relative prediction error and median absolute relative prediction error of 4.0 and 9.4%, respectively in the range of 10-5000 ng/mL. The method showed good accuracy and precision. The presented statistical framework could be used to choose the best model for heteroscedastic calibration data for analytes like propofol with wide range of expected concentration.

Simultaneous determination of propofol and remifentanil in rat plasma by liquid chromatography-tandem mass spectrometry: application to preclinical pharmacokinetic drug-drug interaction analysis.

Propofol (Pro) is an ultra-short-acting hypnotic agent used for general anesthesia that has no analgesic properties. Remifentanil (Rem) is an ultra-short-acting opioid administered concomitantly as an analgesic with Pro. To evaluate the pharmacokinetic interactions between Pro and Rem, we developed and validated a method combining high-performance liquid chromatography with tandem mass spectrometry for simultaneous determination of Pro and Rem. The proposed method was successfully used to study the pharmacokinetic interactions of Pro and Rem coadministered to rats.

高速液体クロマトグラフィー─蛍光検出法を用いたヒト血漿中プロポフォール濃度測定法の確立─

高速液体クロマトグラフィー─蛍光検出法を用いたヒト血漿中プロポフォール濃度測定法の確立─

Estimation of Pharmacokinetics of Propofol in Indian Pateints by HPLC Method

A quick and sensitive reversed phase high performance liquid chromatography (HPLC) method has been developed in Indian surgical patients to determine the concentration of Propofol In human plasma. Propofol can be isolated from human plasma by adding 1ml precipitating solution which consists of acetonitrile and perchloric acid (67:33) mixture, which also contains dibutylpthalate (1mg/ml) as an internal standard. The sample is mixed for two minute on a vortexer. The plasma substance precipitated by acetonitrile and perchloric acid are further separated by centrifugation. The supernatant is directly injected into the HPLC system with the help of autosampler. The analysis was carried out using column 250 × 4.6 mm column packed with10-μm Spherisorb reversed phase octadecyl silane particles (C 18 ). The 500ml of mobile phase (67:33:0.04) consisted of 335ml of acetonitrile and 165ml of distilled water and 200μl of acetic acid maintaining the pH 4.0.The flow rate of the mobile phase was 1.5ml/ min. propofol was monitored by a UV detector at a 270nm wavelength. The limit of detection of propofol (in human plasma) was found to be 0.0001μg/ml while limit of quantification was found to be 0.001μg/ml for a 20ul injection volume.

Pharmacokinetic and Pharmacodynamic Interactions of Ethanol and Propofol in Rabbits

Propofol is a short-acting intravenous anesthetic which is rapidly metabolized by glucuronidation and ring hydroxylation catalyzed by cytochrome P450. In clinical trials, it was found that patients receiving both ethanol and propofol injection in the surgery awoke significantly earlier than those who were injected propofol alone. To investigate pharmacokinetic and pharmacodynamic interactions of propofol and ethanol, propofol was injected alone and in combination with ethanol to rabbits. Propofol was injected intravenously at a dose rate of 15 mg kg−1. Ethanol was injected intraperitoneally at a dose rate of 2.5 mg kg−1. An LC assay with native fluorescence detection was developed and validated for determining the concentration of propofol in rabbit plasma and the effect of co-injected ethanol on the plasma pharmacokinetics of propofol in rabbits. Co-injection of ethanol decreased the maximum plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC0–∞) of propofol by 53.28 and 53.42%, respectively, as compared to the control (P < 0.001). Concomitant ethanol also caused a 66.67% increase in plasma clearance (CL) (P < 0.001). These may partially explain the finding that co-injected ethanol reduced the anesthetic effect of propofol by introducing hepatic microsomal drug-metabolizing enzymes activity in rabbits.

Cerebrospinal fluid and plasma propofol concentration during total intravenous anaesthesia of patients undergoing elective intracranial tumor removal

The aim of this paper is to compare the propofol concentration in plasma and cerebrospinal fluid (CSF) in patients scheduled for intracranial tumor removal and anaesthetized using propofol as part of a total intravenous anaesthesia technique. Twenty-seven patients (ASA I-II) scheduled for elective intracranial tumor removal were studied. Anesthesia was induced with 2 mg/kg propofol for 5 min and infused at 10 mg/(kg x h) for 5 min and then stopped. CSF and arterial blood were collected simultaneously before infusion of propofol and at different time points after infusion of propofol according to bispectral index (BIS) values. Concentrations of propofol in plasma and CSF were measured by HPLC with fluorescence detection. The correlation coefficient and regression equation between plasma and CSF concentration of propofol were worked out by linear simple regression. The propofol CSF concentration that we measured was 1.46% of the plasma concentration. The coefficient of relation between plasma and CSF concentration was 76.7%. The propofol CSF concentration was positively correlated with and much lower than the plasma concentration. Discrepancies may result from high plasma protein binding of propofol, intracranial pathology and sampling volume.

A new method for the quantitation of propofol in human plasma: efficient solid-phase extraction and liquid chromatography/APCI-triple quadrupole mass spectrometry detection

A new method for the quantitation of propofol in human plasma: efficient solid-phase extraction and liquid chromatography/APCI-triple quadrupole mass spectrometry detection