Determination of methylphenidate and its main metabolite in plasma by gas chromatography-chemical ionization mass spectrometry.

Nakajima, Katsuyoshi; Kotaki, Hajime; Saitoh, Yurika; Nakagawa, Fujio

doi:10.1248/cpb.34.1701

Cited by 19 publications

(10 citation statements)

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“…In the first death cases related to ethylphenidate reported by Krueger et al, it was suspected that the cardiovascular side effects may have contributed to the death especially as the deceased was found to have mitral valve endocarditis [18]. An added complication is that the concentrations of ethylphenidate may have been underreported due to instability, although ethylphenidate has not been subject to stability studies in blood or plasma, methylphenidate has been shown to be unstable in both blood and plasma due to hydrolysis by blood esterases [20][21][22][23]. From the results of these studies it appears that the best method of maintaining stability of ethylphenidate is most likely to be via storage at temperatures less than 4°C and in sodium fluoride (NaF) containing tubes [24] although this would need to be confirmed with stability studies.…”

Section: Resultsmentioning

confidence: 99%

Seven fatalities associated with ethylphenidate

Maskell

Smith

Cole

et al. 2016

Forensic Science International

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Ethylphenidate is a stimulant novel psychoactive substance that is an analogue of the prescription drug methylphenidate (Ritalin ®. Methylphenidate is used commonly for the treatment of attention deficit hyperactivity disorder. Due to its stimulant effects ethylphenidate is being abused. There is a single case report of a death associated with ethylphenidate in Germany, and a case series of 19 deaths in the East of Scotland, but otherwise, the contribution of ethylphenidate to death is poorly documented. We report the analytical results of 7 cases (between February 2013 and January 2015) in which ethylphenidate was detected and quantitated with a validated liquid chromatography tandem mass spectrometry method (LC-MS/MS). The individuals (all male) ranged in age from 23 to 49 years (median 25 years). The concentration of ethylphenidate in the cases ranged from 0.026 mg/L to 2.18 mg/L in unpreserved post-mortem femoral blood. Only one case had ethylphenidate present as a sole drug. All other cases had at least 2 other drug classes present (benzodiazepines, heroin, methadone antipsychotics, other new psychoactive compounds). Ethylphenidate toxicity was the sole contribution to the cause of death in one case. Hanging was the cause of death in 2 cases, with the other 4 cases being reported as having occurred due to mixed drug toxicity. These data will further help with the interpretation of post-mortem ethylphenidate levels.

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Section: Resultsmentioning

confidence: 99%

Seven fatalities associated with ethylphenidate

Maskell

Smith

Cole

et al. 2016

Forensic Science International

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“…Stability-Several previous studies have demonstrated that the stability of MPH in plasma was not problematic when the samples were processed within 0.5 h after thawing [9,10,13]. Therefore, during the development of this assay only the stability of the MPH and MPPA derivatives was determined by comparing the peak areas of 0 h and 24 h after the respective derivatization reactions.…”

Section: Assay Validationmentioning

confidence: 99%

“…A number of analytical methods using mass spectrometry (MS) as the mode of detection have been reported for the determination of MPH in plasma and other tissues, and have been considered the methods of choice [5][6][7][8][9][10][11][12][13]. These methods are generally both reliable and sensitive, but are not always practical due to the associated costs and availability of MS instrumentation as well as the requisite expertise in operating MS systems.…”

Section: Introductionmentioning

confidence: 99%

A novel HPLC fluorescence method for the quantification of methylphenidate in human plasma

Zhu

Wang

Patrick

et al. 2007

Journal of Chromatography B

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A number of analytical methods have been established to quantify methylphenidate (MPH). However, to date no HPLC methods are applicable to human pharmacokinetic studies without the use of mass spectrometry (MS) detection. We developed a sensitive and reliable HPLC-fluorescence method for the determination of MPH in human plasma using 4-(4,5-diphenyl-1H-imidazol-2-yl) benzoyl chloride (DIB-Cl) as the derivatizing agent. An established GC-MS method was adopted in this study as a comparator assay. MPH was derivatized DIB-Cl, and separated isocratically on a C18 column using a HPLC system with fluorescence detection (λex: 330 nm, λem: 460 nm). The lower limit of determination was found to be 1 ng/mL. A linear calibration curve was obtained over the concentrations ranging from 1 to 80 ng/mL (r=0.998). The relative standard deviations of intra-day and inter-day variations were ≤ 9.10 % and ≤ 7.58 %, respectively. The accuracy ranged between 92.59 % and 103.06 %. The method was successfully applied to the pharmacokinetic study of a subject who received a single oral dose (0.3 mg/kg) of immediate-release MPH and yielded consistent results with that of the GC-MS method. This method is the first HPLC assay with non-MS detection providing sufficient reliability and sensitivity for both pre-clinical and clinical studies of MPH.

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“…In this regard, preliminary work has shown that interspecies differences exist in the ability of plasma esterases to hydrolyze MPH. 24 Enantioselectivity in the hydrolysis of MPH by blood esterases has previously not been investigated since previous methods were not enantioselective. The recent development of an enantioselective method in our laboratories now makes such investigations possible.…”

Section: Introductionmentioning

confidence: 99%

In vitro hydrolysis of RR,SS‐threo‐methylphenidate by blood esterases—differential and enantioselective interspecies variability

et al. 1991

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Enantioselective in vitro hydrolysis of methylphenidate (MPH) by the blood esterases of seven mammalian species is reported. The species included rats, rabbits, dogs, cattle, horses, monkeys, and humans. In vitro incubations up to 8 h were carried out in plasma, red blood cells, and whole blood of the various species. Enantioselective differences were evident among the different species on comparison of the data obtained from the three biological fluids. The esterases present in plasma appeared to show greater activity in the hydrolysis of MPH in all species where comparison with the other two biofluids was possible. Only in the case of humans did esterases present in plasma and red blood cells demonstrate opposite enantioselectivity in the hydrolysis of MPH. Thus after 8 h incubation, the RR-MPH/SS-MPH ratios in plasma and red blood cells were 0.31 and 1.16, respectively.

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Determination of methylphenidate and its main metabolite in plasma by gas chromatography-chemical ionization mass spectrometry.

Cited by 19 publications

References 0 publications

Seven fatalities associated with ethylphenidate

Seven fatalities associated with ethylphenidate

A novel HPLC fluorescence method for the quantification of methylphenidate in human plasma

In vitro hydrolysis of RR,SS‐threo‐methylphenidate by blood esterases—differential and enantioselective interspecies variability

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