Analytically Confirmed Intoxication by 4-Fluoromethylphenidate, an Analog of Methylphenidate.

4-Fluoromethylphenidate (4F-MPH) is an halogenated derivative of methylphenidate (MPH), a re-uptake inhibitor for dopamine and norepinephrine used for the treatment of attention deficit hyperactivity disorders. In the last few years, several compounds structurally related to MPH have been marked as new psychoactive substances (NPS) with stimulating and euphoric effects similar to the parent drug, but with more dopaminergic activity. This report represents the first case of an analytically confirmed non-fatal intoxication by 4F-MPH. A 26-year-old female was admitted to the emergency department with neuropsychiatric and cardiologic symptoms that lasted for a week, during which she sniffed a powder named 4F-MPH acquired as entactogen on the Internet. The patient required sedation with intravenous diazepam and was discharged two days later with a prescription of promazine and quetiapine. The seized product was analytically characterized by gas chromatography-mass spectrometry, liquid chromatography high-resolution mass spectrometry and nuclear magnetic resonance. These analyses confirmed the composition of the product as a 4F-MPH diastereomeric (±)-threo and (±)-erythro mixture, with a large preponderance of the active (±)-threo isomer. A minimal validation, intended for rare analytes, was performed for the quantification of 4F-MPH in the biological samples by liquid chromatography-tandem mass spectrometry. Accuracy (bias) and precision were within ±15% for both blood and urine. The blood and urine concentration of (±)-threo 4F-MPH were 32 ng/mL and 827 ng/mL, respectively. Analyses for classic drugs (opiates, methadone, cocaine, cannabis metabolites, amphetamines, ecstasy and LSD), ethanol, qualitative full screen by gas chromatography-mass spectrometry and targeted analysis for 50 NPS by liquid chromatography-tandem mass spectrometry tested negative; comorbidities were excluded, too. Based on these data, it can be assumed that the clinical manifestations were due to 4F-MPH only.

L- and D-threo ethylphenidate concentrations, pharmacokinetics, and pharmacodynamics in horses.

Ethylphenidate is a psychostimulant and analog of the commonly prescribed compound, methylphenidate (Ritalin®). There are a limited number of studies describing the disposition and pharmacologic/toxicological effects of ethylphenidate in any species. The abuse potential in equine athletes along with the limited data available regarding administration in horses necessitates further study. The objectives of the current study were to describe drug concentrations, develop an analytical method that could be used to regulate its use, and describe the pharmacodynamic effects of ethylphenidate in horses. To that end, 12 horses were randomized into 3 dose groups (intravenous: 10 mg or 40 mg, oral: 40 mg). Ethylphenidate was administered and blood and urine samples were collected prior to and for up to 72 hours post drug administration. Concentrations of D-threo ethylphenidate and the metabolite ritalinic acid were measured using Liquid Chromatography-tandem Mass Spectrometry. L-threo ethylphenidate concentrations were estimated from D-threo ethylphenidate concentrations. Serum concentrations of ethylphenidate were below detectable levels by 8, 18, and 12 hours following intravenous administration of 10 mg and 40 mg and oral administration of 40 mg, respectively. Ritalinic acid was non-detectable at 72 hours in the group that received a 10-mg intravenous and 40-mg oral dose of ethylphenidate. Ritalinic acid concentrations were below the LOQ at 72 hours following intravenous administration of 40 mg of ethylphenidate. While the number of animals per dose group were small, no stimulatory behavior or significant changes in heart rate were noted. Untoward effects including gastrointestinal adverse effects were noted in all dose groups.

Metabolic Patterns of Fentanyl, Meperidine, Methylphenidate, Tapentadol and Tramadol Observed in Urine, Serum or Plasma.

Drug testing is a useful tool to identify drug use or monitor adherence to prescription drugs. The interpretation of drug results can be complicated based on the pattern and proportional concentrations of drugs and/or drug metabolite(s). The purpose of this retrospective study was to detect the positivity rates and metabolic patterns of five prescription drugs, including fentanyl, meperidine, methylphenidate, tapentadol and tramadol. Retrospective data were retrieved from the laboratory information system in a national reference laboratory. Drug testing was performed using four mass spectrometry methods that were validated for clinical use. For urine specimens, the positivity rate was the highest for methylphenidate (62.3%, n = 2,489), followed by tramadol (43.7%, n = 3,483), fentanyl (41.9%, n = 4,657), tapentadol (37.9%, n = 736) and meperidine (8.3%, n = 138). Among positive samples, both parent drug and metabolite(s) was detectable in 94.9% of meperidine samples, 94.5% of tramadol samples, 93.8% of fentanyl samples, 89.9% of methylphenidate and 86.6% of tapentadol samples. For serum or plasma specimens, the positivity rate was the highest for tapentadol (75.0%, n = 39), followed by methylphenidate (74.2%, n = 569), fentanyl (53.6%, n = 113), meperidine (41.9%, n = 18) and tramadol (28.9%, n = 213). Similar metabolic patterns were found in serum or plasma. Of positive results, both parent drug and metabolite(s) were found in 94.7% of fentanyl samples, 83.3% of meperidine samples, 79.6% of methylphenidate samples, 53.8% of tapentadol samples and 44.1% of tramadol samples. Our data demonstrates the metabolic patterns of five drugs from a random urine or serum/plasma collection in patients that have been prescribed these medications. The data presented can be used to guide clinicians in determining drug adherence by assessing the positivity rates of the parent drug and corresponding metabolite(s).

Pharmacological Cognitive Enhancement in Healthy Individuals: A Compensation for Cognitive Deficits or a Question of Personality?

The ongoing bioethical debate on pharmacological cognitive enhancement (PCE) in healthy individuals is often legitimated by the assumption that PCE will widely spread and become desirable for the general public in the near future. This assumption was questioned as PCE is not equally save and effective in everyone. Additionally, it was supposed that the willingness to use PCE is strongly personality-dependent likely preventing a broad PCE epidemic. Thus, we investigated whether the cognitive performance and personality of healthy individuals with regular nonmedical methylphenidate (MPH) use for PCE differ from stimulant-naïve controls. Twenty-five healthy individuals using MPH for PCE were compared with 39 age-, sex-, and education-matched healthy controls regarding cognitive performance and personality assessed by a comprehensive neuropsychological test battery including social cognition, prosocial behavior, decision-making, impulsivity, and personality questionnaires. Substance use was assessed through self-report in an interview and quantitative hair and urine analyses. Recently abstinent PCE users showed no cognitive impairment but superior strategic thinking and decision-making. Furthermore, PCE users displayed higher levels of trait impulsivity, novelty seeking, and Machiavellianism combined with lower levels of social reward dependence and cognitive empathy. Finally, PCE users reported a smaller social network and exhibited less prosocial behavior in social interaction tasks. In conclusion, the assumption that PCE use will soon become epidemic is not supported by the present findings as PCE users showed a highly specific personality profile that shares a number of features with illegal stimulant users. Lastly, regular MPH use for PCE is not necessarily associated with cognitive deficits.

Evaluation of concomitant methylphenidate and opioid use in patients with pain.

Methylphenidate is a central nervous system simulant that is used for management of opioid-induced sedation. Sparse data exist regarding use patterns of methylphenidate and opioids in patients with pain. This retrospective data analysis evaluated concomitant methylphenidate and opioid use from physician-reported medication lists and in urine specimens of patients with pain. All specimens were analyzed and quantified with LC-MS-MS. Concomitant methylphenidate and opioid use (e.g., sample population) were compared with a baseline population of patients taking opioids. There were 3,326 patients with physician-reported use of methylphenidate. Of these, 1,089 patients were tested for the presence of methylphenidate in urine. Methylphenidate was positive in urine for 551 patients (detection rate of 50.6%). Ritalinic acid was positive in 776 patients (detection rate of 71.3%). The current study observed differences in the use pattern of methylphenidate based on opioid type. Physician-reported use revealed methadone had the highest percent difference between the sample and baseline populations (77%, P ≤ 0.05). Fentanyl, morphine and hydromorphone also had higher percent differences of 19.6, 25.3 and 32.3%, respectively. Further studies need to examine the apparent discrepancies between the physician-reported medication lists and urine drug testing of concomitant methylphenidate and opioid use in patients with pain.

Analysis of new designer drugs and common drugs of abuse in urine by a combined targeted and untargeted LC-HR-QTOFMS approach.

The development of a liquid chromatography high-resolution mass spectrometry quadrupole-time-of-flight (LC-HRMS-QTOF) method for the analysis of new stimulant designer drugs (e.g. phenethylamine, amphetamine, cathinone and piperazine derivatives) and common drugs of abuse (e.g. ketamine and ritalinic acid) in urine is reported. Sample preparation was carried out by a fast and convenient salting-out liquid-liquid extraction (SALLE) procedure. The data was generated by a preferred target list combined with untargeted data-dependent acquisition recording additional sample information (i.e. not listed metabolites of target compounds or not database-stored drugs). The identification is realised by a fully automated data extraction algorithm, taking into account accurate mass spectra, fragment masses and retention times. Method validation comprised selectivity, linearity, accuracy, stability, determination of the limit of detection (LOD) and limit of quantification (LOQ) and evaluation of matrix effects and recoveries for a total set of 39 compounds. Acceptable quantitative results were obtained for 35 of the 39 analytes. Exemplarily, application of the additional untargeted data-dependent acquisition mode enabled the identification of metabolites of the preferred target list compounds ketamine and methylenedioxypyrovalerone (MDPV) without use of reference standards. Therefore, improvement of the database is feasible with every positive library hit. The approach presented here provides a very useful tool for the combined targeted and untargeted analysis of drugs of abuse in biological matrices such as urine.

Determination of amphetamine and methylphenidate in exhaled breath of patients undergoing attention-deficit/hyperactivity disorder treatment.

OBJECTIVES: It has been discovered recently that exogenous substances are detectable in exhaled breath after intake. Exhaled breath therefore constitutes a new possible matrix in clinical pharmacology and toxicology. The present work was aimed at exploring this possibility further by a study on patients treated for attention-deficit/hyperactivity disorder with D-amphetamine and methylphenidate. METHODS: Thirteen patients (age range: 32-61 years; 5 women) were included in the study, and breath and urine samples were collected at different times in the dose interval. Analyses of breath and urine samples were done with liquid chromatography-mass spectrometry methods. Urine was examined for amphetamine, methylphenidate, and its metabolite ritalinic acid. RESULTS: Among the 9 patients who received D-amphetamine medication in daily doses of 20-100 mg, amphetamine was detected in all subjects in amounts ranging from 1200 to 30,800 picogram per filter. Among 8 patients receiving methylphenidate medication in daily doses of 80-400 mg, it was detected and quantified in 7 of the cases in amounts ranging from 150 to 10,400 picogram per filter and ritalinic acid was detected and quantified in 3 of the cases ranging from 35 to 360 picogram per filter. In 1 case, methylphenidate was only detectable in breath and urine, whereas ritalinic acid was quantifiable in urine, which could indicate noncompliance, with the 4 hours of dose regimen prescribed. In a number of cases, the sampling was performed 24 hours after the last dose intake. Identification of amphetamine and methylphenidate was based on correct chromatographic retention time and correct product ion ratio with detection performed in selected reaction monitoring mode. CONCLUSIONS: The results confirm that amphetamine is present in exhaled breath after intake and demonstrate for the first time the presence of methylphenidate and ritalinic acid after its intake. This gives further support to the potential use of exhaled breath for detecting drug intake.

[Methylphenidate in the treatment of children with attention-deficit hyperactivity disorder: monitoring in biological matrices]. / Metilfenidato en el tratamiento del trastorno de déficit de atención con hiperactividad en pediatría: monitorización en matrices biológicas.

Attention-deficit hyperactivity disorder (ADHD) has emerged in the last few years as the most commonly diagnosed and treated psychiatric disorder in the paediatric population. In 1980's, methylphenidate (MFD) a psychomotor stimulant drug, was approved in Spain for the symptomatic therapy of ADHD. Since then, MFD has become one of the most extensively prescribed and studied treatment for ADHD both in children and adults. In this paper, the main pharmacological issues of MFD are reviewed, focusing on its pharmacokinetics in conventional (blood and urine) and non-conventional (hair, oral fluid and sweat) biological matrices, its pharmaceutical preparations, therapeutic levels and side effects.

Determination of methylphenidate and its metabolite ritalinic acid in urine by liquid chromatography/tandem mass spectrometry.

Methylphenidate (MPH) is a drug that is licensed for treatment of ADHD and also narcolepsy. Monitoring of the parent drug and its major metabolite ritalinic acid (RA) in urine is considered necessary to ensure compliance with treatment programmes. A rapid, simple and sensitive liquid chromatography/tandem mass spectrometry (LC-MS/MS) assay was developed for the determination of MPH and its metabolite RA in human urine. After urine was diluted with water, methylphenidate, the major metabolite ritalinic acid, and d6-amphetamine as the internal standard were resolved on a PFP propyl column using gradient elution of 0.02% ammonium formate and acetonitrile. The total analysis time was 13.5 min. The three compounds were detected using electrospray ionisation in the positive mode. Standard curves were linear over the concentration range 5-5000 µg/L (r>0.997), bias was ≤ ±20%, intra- and inter-day coefficients of variation (imprecision) were <8% and the limit of detection was 5 µg/L. The limit of quantitation was set at 100 µg/L. Matrix effects were up to 140% but these were accounted for by the internal standard. The assay is being used successfully in clinical practice to enhance the safe and effective use of methylphenidate.

Transdermal and oral dl-methylphenidate-ethanol interactions in C57BL/6J mice: transesterification to ethylphenidate and elevation of d-methylphenidate concentrations.

We tested the hypothesis that C57BL/6J mice will model human metabolic interactions between dl-methylphenidate (MPH) and ethanol, placing an emphasis on the MPH transdermal system (MTS). Specifically, we asked: (1) will ethanol increase d-MPH biological concentrations, (2) will MTS facilitate the systemic bioavailability of l-MPH, and (3) will l-MPH enantioselectively interact with ethanol to yield l-ethylphenidate (l-EPH)? Mice were dosed with MTS (» of a 12.5 cm(2) patch on shaved skin) or a comparable oral dl-MPH dose (7.5 mg/kg), with or without ethanol (3.0 g/kg), and then placed in metabolic cages for 3 h. MPH and EPH isomer concentrations in blood, brain, and urine were analyzed by gas chromatographic-mass spectrometry monitoring of N-(S)-prolylpiperidyl fragments. As in humans, MTS greatly facilitated the absorption of l-MPH in this mouse strain. Similarly, ethanol led to the enantioselective formation of l-EPH and to an elevation in d-MPH concentrations with both MTS and oral MPH. Although only guarded comparisons between MTS and oral MPH can be made due to route-dependent drug absorption rate differences, MTS was associated with significant MPH-ethanol interactions. Ethanol-mediated increases in circulating concentrations of d-MPH carry toxicological and abuse liability implications should this animal model hold for ethanol-consuming attention-deficit hyperactivity disorder patients or coabusers.

Liquid chromatography-electrospray ionization mass spectrometry determination of methylphenidate and ritalinic acid in conventional and non-conventional biological matrices.

A procedure based on liquid chromatography-electrospray ionization mass spectrometry is described for determination of methylphenidate (MPH) and its principal metabolite ritalinic acid (RA) in plasma, urine, oral fluid and sweat using 3,4-methylendioxypropylamphetamine (MDPA) as internal standard. Aliquots of 100microL biological fluids and sweat patch were initially treated with acetonitrile, centrifuged, and clear supernatants evaporated and redissolved in 10mM ammonium acetate. Chromatography was performed on a reversed-phase column using a gradient of 10mM ammonium acetate and acetonitrile as a mobile phase at a flow rate of 1mL/min. Separated analytes were confirmed and quantified by positive electrospray ionization mass spectrometry and selected ion monitoring acquisition mode. Limits of quantifications were 1ng/mL plasma, 1ng/sweat patch, 0.5ng/mL oral fluid and urine for MHF; 1ng/mL plasma and oral fluid, 1ng/sweat patch, 0.5ng/mL urine for RA using 100microL biological fluids or one sweat-patch per assay. Calibration curves were linear over the calibration ranges for both MPH and RA, with r(2)>0.99. At three concentrations spanning the linear dynamic range of the assay, mean recoveries ranged between 67.9-90.3% for MPH and 36.3-92.4% for RA in the different biological matrices. This method was applied to therapeutic monitoring of MHP and RA in conventional and non-conventional biological matrices from individuals in drug treatment.

Enantiospecific gas chromatographic-mass spectrometric analysis of urinary methylphenidate: implications for phenotyping.

A chiral derivatization gas chromatographic-mass spectrometric (GC-MS) method for urine methylphenidate (MPH) analysis was developed and validated to investigate preliminary findings regarding a novel MPH poor metabolizer (PM). Detection was by electron impact (EI) ionization-selected ion monitoring of the N-trifluoroacetylprolylpiperidinium fragments from MPH and the piperidine-deuterated MPH internal standard. The PM eliminated approximately 70 times more l-MPH in urine (9% of the dose over 0-10h), and approximately 5 times more of the d-isomer (10% of the dose), than the mean values determined from 10 normal metabolizers of MPH. Only minor amounts of the metabolite p-hydroxy-MPH were found in the urine of both the PM and normal metabolizers, while the concentration of MPH lactam was not high enough to be detectable. The described method indirectly gauges the functional carboxylesterase-1 status of patients receiving MPH based on the evaluation of relative urine concentrations of d-MPH:l-MPH. Clinical implications concerning rational drug selection for an identified or suspected MPH PM are discussed.

Liquid chromatography-tandem mass spectrometry method for the simultaneous analysis of multiple hallucinogens, chlorpheniramine, ketamine, ritalinic acid, and metabolites, in urine.

A validated method for the simultaneous analysis of multiple hallucinogens, chlorpheniramine, ketamine, ritalinic acid, and several metabolites is presented. The procedure comprises a sample clean-up step, using mixed-mode solid-phase extraction followed by liquid chromatography (LC)-tandem mass spectrometry analysis. Chromatographic separation was achieved using a Sunfire C(8) column eluted with a mixture of formate buffer, methanol, and acetonitrile. The applied LC gradient ensured the elution of all the drugs examined within 14 min and produced chromatographic peaks of acceptable symmetry. Selectivity of the method was achieved by a combination of retention time and two precursor-product ion transitions for the non-deuterated analogues. Validation of the method was performed using 500 microL of urine. The limits of quantification (LOQ) for LSD and 2-oxo-3-hydroxy-LSD were 0.05 and 1 ng/mL, respectively, and ranged, for the other hallucinogens, from 0.5 to 10 ng/mL. Linear and quadratic regression was observed from the LOQ of each compound to 12.5 ng/mL for LSD, 50 ng/mL for 2-oxo-3-hydroxy-LSD and 500 ng/mL for the others (r(2) > 0.99). Precision for the QC samples, spiked at a minimum of two concentrations, was calculated [%CV and %bias < 20% for most of the compounds, except for bufotenine and cathinone (%bias < 24%), and ibogaine (%bias < 30%)]. Extraction was found to be both reproducible and efficient with recoveries > 87% for all the analytes. Furthermore, the processed samples were demonstrated to be stable in the autosampler for at least 24 h. Finally, the validated method was applied to the determination of chlorpheniramine, ketamine, LSD, and psilocin in authentic urine samples.

Quantitative mass spectrometric determination of methylphenidate concentration in urine using an electrospray ionization source integrated with a polymer microchip.

We have demonstrated the use of a simple microfabricated electrospray ionization source for coupling microfluidic chips to mass spectrometry (MS). A polymer-based microchip, coupled to a triple quadrupole mass spectrometer, has been employed for direct infusion quantitative bioanalysis of methylphenidate (Ritalin) extracted from human urine samples. The approach used a microfabricated polymer electrospray emitter to couple a microfluidic channel to a stable electrospray ionization source. The microchip was fabricated from cycloolefin plastic plate by hot embossing and thermal bonding. This microfluidic chip contained two independent microfluidic channels, integrated with two corresponding electrospray emitters and an internal gold electrode. Liquid-liquid extraction was used to prepare urine samples, spiked with methylphenidate. A trideuterated analogue of methylphenidate (methylphenidate-d(3)) was used as the internal standard for the analysis. The system showed good electrospray stability and reproducibility with different spray tips. Four different electrospray tips were used to analyze the same sample, and the results showed very small variation with a relative standard deviation of 1.4%. A standard curve prepared for methylphenidate in urine (R(2) = 0.999) was linear over the range of 0.4-800 ng/mL. The precision of the quality control samples for three different concentrations ranged from 19.1% at 20 ng/mL, 3.2% at 200 ng/mL, to 3.5% at 667 ng/mL while the accuracy was 96.3% at 20 ng/mL, 101.2% at 200 ng/mL, and 101.6% at 667 ng/mL. No system carryover was detected even when the same device was used for sequential analysis. These results suggest the potential of this microdevice for MS-based quantitative analysis in drug discovery and development.

Urinary screening for methylphenidate (Ritalin) abuse: a comparison of liquid chromatography-tandem mass spectrometry, gas chromatography-mass spectrometry, and immunoassay methods.

OBJECTIVE: To develop a routine method for detecting methylphenidate (Ritalin) use among drug abusers using liquid chromatography-tandem mass spectrometry (LC/MS/MS). The new methodology was designed to replace less reliable and/or more expensive and time-consuming techniques (GC/MS and ELISA) currently employed in our laboratory, and to provide a combined one-step screening and confirmation LC/MS/MS method. DESIGN AND METHODS: Because methylphenidate abuse is very prevalent in Saskatchewan, there is a demand to provide high volume urine screening both to detect abuse, and to monitor compliance. Random urine samples sent for drugs of abuse testing, standards, and controls were diluted 1:100 in methanol. Diluted specimens were injected directly into an Agilent 1100 liquid chromatograph coupled to a Sciex API 2000 mass spectrometer. The method utilized selected reaction monitoring (SRM) as well as an electrospray ionization source (EIS) to detect both urinary methylphenidate and the more prevalent metabolite, ritalinic acid (RA). RESULTS: There appeared to be little or no sacrifice in sensitivity because the higher dilutions exhibited much less matrix effect. Limit of quantitation (LOQ) for methylphenidate was 100 nM and 500 nM for RA. Linear calibration curves from 100 to 1000 nM for Ritalin and 500 to 5000 nM for RA were acquired. Imprecision of spiked and true specimens did not exceed 10% and at the LOQ, it was less than 20%. CONCLUSIONS: A rapid, sensitive, reliable, and highly specific method by LC/MS/MS for detecting methylphenidate and its metabolite, RA, were developed. Both the cost and performance of the LC/MS/MS method were superior to GC/MS or ELISA, and it allows use of a single rapid procedure for both screening and confirmation.

An enzyme-linked immunosorbent assay (ELISA) for methylphenidate (Ritalin ) in urine.

A direct enyzme-linked immunosorbent assay (ELISA) for urinary immunoreactive methylphenidate (Ritalin), in which a standard 96-well microtiter plate is used, is described. For this ELISA, a methylphenidate-thyroglobulin conjugate is immobilized to the microtiter plate and competes with methylphenidate in the standard or urine sample for antibody-binding sites. After washing, the sheep methylphenidate antibody bound to immobilized methylphenidate is detected with peroxidase-labelled goat antisheep IgG. Following a further wash, tetramethylbenzidine is added, color is developed, and the plate is read at 450 nm on an ELISA plate reader. This method is unaffected by drugs of abuse and is suitable for routine use in the toxicology laboratory.

A device for automated direct sampling and quantitation from solid-phase sorbent extraction cards by electrospray tandem mass spectrometry.

A new solid-phase extraction (SPE) device in the 96-well format (SPE Card) has been employed for automated off-line sample preparation of low-volume urine samples. On-line automated analyte elution via SPE and direct quantitation by micro ion spray mass spectrometry is reported. This sample preparation device has the format of a microtiter plate and is molded in a plastic frame which houses 96 separate sandwiched 3M Empore sorbents (0.5-mm-thickness, 8-microm particles) covered on both sides by a microfiber support material. Ninety-six discrete SPE zones, each 7 mm in diameter, are imbedded into the sheet in the conventional 9-mm pitch (spacing) of a 96-well microtiter plate. In this study one-quarter of an SPE Card (24 individual zones) was used merely as a convenience. After automated off-line interference elution of applied human urine from 24 samples, a section of SPE Card is mounted vertically on a computer-controlled X, Y, Z positioner in front of a micro ion spray direct sampling tube equipped with a beveled tip. The beveled tip of this needle robotically penetrates each SPE elution zone (sorbent disk) or stationary phase in a serial fashion. The eluted analytes are sequentially transferred directly to a microelectrosprayer to obtain tandem mass spectrometric (MS/MS) analysis. This strategy precludes any HPLC separation and the associated method development. The quantitative determination of Ritalin (methylphenidate) from fortified human urine samples is demonstrated. A trideuterated internal standard of methylphenidate was used to obtain ion current response ratios between the parent drug and the internal standard. Human control urine samples fortified from 6.6 to 3300 ng/mL (normal therapeutic levels have been determined in other studies to be between 50 and 100 ng/mL urine) were analyzed and a linear calibration curve was obtained with a correlation coefficient of 0.9999, where the precision of the quality control (QC) samples ranged from 9.6% at the 24 ng/mL QC level to 1.2% at the 3000 ng/mL QC level, and the accuracy for the four levels of QC samples ranged from 98.1% to 100.3%. The QC samples were prepared at four concentrations which included 24, 240, 1200, and 3000 ng/mL, respectively. The run time per sample in this work was 1.5 min not including the sample preparation time.