Eloisa Comiran

Lisdexamfetamine: A pharmacokinetic review

Lisdexamfetamine (LDX) is a d-amphetamine (d-AMPH) pro-drug used to treat Attention Deficit and Hyperactivity Disorder (ADHD) and Binge Eating Disorder (BED) symptoms. The in vivo pharmacodynamics of LDX is the same as that of its active product d-AMPH, although there are a few qualitative and quantitative differences due to pharmacokinetics. Due to the specific pharmacokinetics of the long-acting stimulants, this article revises the pharmacokinetic studies on LDX, the newest amphetamine pro-drug. The Medline/Pubmed, Science Direct and Biblioteca Virtual em Saúde (Lilacs and Ibecs) (2007-2016) databases were searched for articles and their list of references. As for basic pharmacokinetics studies, since LDX is a newly developed medication, there are few results concerning biotransformation, distribution and the use of different biological matrices for analysis. This is the first robust review on this topic, gathering data from all clinical pharmacokinetics studies available in the literature. The particular pharmacokinetics of LDX plays a major role in studying this pro-drug, since this knowledge was essential to understand some reports on clinical effects in literature, e.g. the small likelihood of reducing the effect by interactions, the effect of long duration use and the still questionable reduction of the potential for abuse. In general the already well-known pharmacokinetic properties of amphetamine make LDX relatively predictable, simplifying the use of LDX in clinical practice.

Simultaneous determination of cocaine/crack and its metabolites in oral fluid, urine and plasma by liquid chromatography-mass spectrometry and its application in drug users

INTRODUCTION A single LC-MS equipment was used to validate three methods for simultaneously analyzing cocaine (COC), benzoylecgonine (BZE), cocaethylene (CE), anhydroecgonine methyl ester (AEME) and anhydroecgonine (AEC) in oral fluid (OF), urine and plasma. METHODS The methods were carried out using a Kinetex HILIC column for polar compounds at 30°C. Mobile phase with isocratic condition of acetonitrile: 13mM ammonium acetate pH 6.0: methanol (55:35:10 v/v/v) at 0.8mL/min flow rate was used. RESULTS After buffer dilution (OF) and protein precipitation (urine and plasma), calibration curve ranges were 4.25-544ng/mL for oral fluid and 5-320ng/mL for urine and plasma with correlation coefficients (r) between 0.9947 and 0.9992. The lowest concentration of the calibration curves were the lower limit of quantification. No major matrix effect could be noted, demonstrating the efficiency of the cleaning procedure. DISCUSSION The methods were fully validated and proved to be suitable for analysis of 124 cocaine and/or crack cocaine users. Among the subjects, 56.5% reported daily use of cocaine in the previous three months. Results show a high prevalence of the analytes, with BZE as the most prevalent (94 cases), followed by COC (93 cases), AEC (70 cases), CE (33 cases) and AEME (13 cases). In addition, the concentration of BZE in urine was higher compared to OF and plasma found in the real samples, showing the facility of accumulation in chronic users in matrices with a large detection window.

Detection of ethanol in Brazilian gasoline station attendants

In Brazil, gasoline station attendants are regularly exposed to the ethanol contained in fuel, as well as the one used as the gasoline additive. This study aimed to assess the potential exposure of these workers to fuels, using breathalyzers and oral fluid (OF) analysis by headspace gas chromatography/mass spectrometry (HS-GC/MS). Attendants of 26 gasoline stations were invited to respond to a questionnaire covering the main features of the study population and the profile of drinking and driving behavior, followed by a breath test and OF collection with a Quantisal™ device. All OF samples were analyzed by HS-GC/MS. Ethanol was found in 100% of the OF samples whereas 72.83% had concentrations above the quantification limit of the method (0.00125 g dL−1). Regarding the breath tests, only one exhaled air sample (0.62%) showed a positive result (0.03 mg L−1). The positive results in OF samples and negative results in exhaled air may be explained by the higher sensitivity of OF analysis by HS-GC/MS, when compared to the breathalyzer.

Extraction optimization using Box–Behnken design and method validation for ethanol in oral fluid

In Brazil, routine verification of alcohol use amongst drivers is performed using breath alcohol analyzers and confirmation of ethanol in blood, using the headspace (HS) technique associated with gas chromatography with a flame ionization detector (GC/FID). Oral fluid (OF) is an alternative that, once collected, can be used both for screening and confirmation, and has many advantages. We propose an optimization of the extraction of ethanol from OF using the HS through experimental design and subsequent development and validation of an analytical method using HS-GC/FID and HS-GC/MS (mass spectrometry), using Quantisal® as a collection device. Experimental design was performed using the Box–Behnken design, and the evaluated parameters were heating temperature, stirring time and injection volume. Selectivity, residual effect, matrix effect, linearity, precision, accuracy, limits of detection and quantification, stability and recovery were evaluated in the validation process. The optimized conditions for extraction were: a temperature of 90 °C, an injection volume of 1000 μL, and a stirring time of 7 min. Linearity was obtained with an R2 greater than 0.99. The accuracy for the quality control samples remained within 101.56 and 111.2 of the target concentrations, whilst the precision did not exceed 12% of their relative standard deviations. The developed method showed full viability of performance, proving to be rapid and sensitive, as it does not require sample preparation steps. The HS-GC/MS method had detection limits lower than those of HS-GC/FID, and can be easily applied for routine confirmation of ethanol in drivers.

Method validation and determination of lisdexamfetamine and amphetamine in oral fluid, plasma and urine by LC-MS/MS.

Lisdexamfetamine (LDX) is a long-acting prodrug stimulant indicated for the treatment of attention-deficit/hyperactivity disorder and binge-eating disorder symptoms. In vivo hydrolysis of LDX amide bond releases the therapeutically active d-amphetamine (d-AMPH). Since toxicological tests in biological samples can detect AMPH from the use of some legal medications, efficient methods are needed in order to correctly interpret the results. The aim of this study was to develop and validate an LC-MS/MS method for the simultaneous quantification of LDX and its main biotransformation product AMPH in human oral fluid, plasma and urine. Calibration curve range for both analytes was 1-128 ng/mL in oral fluid and plasma and 4-256 ng/mL in urine, being the lowest concentration the limit of quantification. Accuracy of the determined values of the target analytes for the five control levels ranged from 94.8 to 111.7% for oral fluid, from 91.3 to 100.2% for plasma and from 94.8 to 109.8% for urine. Imprecision for the five control levels did not exceeded 12.8% for oral fluid, 16.2% for plasma and 17.1% for urine. The method developed for the three matrices was validated and was also successfully applied to assess real samples, showing for the first time the detection of LDX in oral fluid.

Assessment of lisdexamfetamine dimesylate stability and identification of its degradation product by NMR spectroscopy

Abstract Lisdexamfetamine dimesylate (LDX), a long-acting prodrug stimulant indicated for the treatment of the attention-deficit/hyperactivity disorder (ADHD), was subjected to forced degradation studies by acid and alkaline hydrolysis and the degradation profile was studied. To obtain between 10–30% of degraded product, acid and alkaline conditions were assessed with solutions of 0.01 M, 0.1 M, 0.5 M, and 1 M of DCl and NaOD. These solutions were analyzed through 1 H NMR spectra. Acid hydrolysis produced no degradation in 0.01 M and 0.1 M DCl and 4.38%, 9.69%, and 17.75% of degradation LDX, respectively, in 0.5 M, 1 M (4h) and 1 M (4 + 12 h) DCl. And alkaline hydrolysis produced no degradation in 0.01 M and 0.1 M DCl and a degradation LDX extension of 8.5%, 14.30%, and 22.91%, respectively, in 0.5 M, 1 M (4h) and 1 M (4 + 12 h) NaOD. LDX solutions subjected to 1 M (4 + 12 h) acid and alkaline hydrolysis were evaluated by NMR spectra (1 H NMR, 13 C NMR, HSQC and HMBC). LDX degradation product (DP) was identified and its structure elucidated as a diastereoisomer of LDX: (2R)-2,6-diamino-N-[(2S)-1-phenylpropan-2-yl] hexanamide without their physical separation.

Photodegradation kinetics of lisdexamfetamine dimesylate and structure elucidation of its degradation products by LC-ESI-QTOF

Herein, we investigate the photodegradation of lisdexamfetamine (LDX) in an aqueous solution. The experiment is carried out by exposing the drug in solution to UV radiation for different periods of time during 48 h. The fragmentation pattern of LDX is established, and its two degradation products are identified (DP-01 and DP-02) and structurally characterized via liquid chromatography coupled with hybrid quadrupole time-of-flight electrospray ionization (LC-ESI-QTOF) mass spectrometry. Furthermore, the photodegradation kinetics of LDX is determined via LC-ESI-QTOF (r = 0.9905; k = 0.0204 h−1; and t1/2 = 33.91 h) and RP-LC-CAD (r = 0.9960; k = 0.0234 h−1; and t1/2 = 29.67 h). LDX is found to be unstable in the presence of light under the evaluated conditions.