Kinetic Analysis of Enantiomers of Threo-Methylphenidate and Its Metabolite in Two Healthy Subjects after Oral Administration as Determined by a Gas Chromatographic-Mass Spectrometric Method

Aoyama, Takao; Kotaki, Hajime; Honda, Yoshiyuki; Nakagawa, Fujio

doi:10.1002/jps.2600790602

Cited by 48 publications

(19 citation statements)

References 6 publications

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“…In another study, an oral dose of 1 mg/kg methylphenidate produced plasma levels of 9.3 ng/ml within 15 min (Kuczenski and Segal, 2002). An earlier study reported ∼2 ng/ml plasma levels of methylphenidate following 0.5 mg/kg oral dose, 36 ng/kg following 2 mg/kg dose and 62 ng/ml following 3.5 mg/kg dose (Aoyama et al, 1990). Oral administration of 0.75 mg/kg was predicted to yield peak plasma concentrations between 2 and 9 ng/ml, representing lower limits of the clinical range, whereas a dose of 3 mg/kg was predicted to produce peak plasma concentrations between 30 and 60 ng/ml, corresponding to upper limits of the clinical range (Kuczenski and Segal, 2002).…”

Section: Discussionmentioning

confidence: 98%

Plasma and brain concentrations of oral therapeutic doses of methylphenidate and their impact on brain monoamine content in mice

et al. 2009

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SummaryMethylphenidate is a frequently prescribed stimulant for the treatment of attention deficit hyperactivity disorder (ADHD). An important assumption in the animal models that have been employed to study methylphenidate's effects on the brain and behavior is that bioavailability of methylphenidate in the animal models reflects that in human subjects. From this perspective, the dose and route of administration of methylphenidate assume critical importance because both these factors likely influence rate of uptake, plasma and brain concentrations of the drug. In the present study, plasma and brain concentrations of D-and L-methylphenidate and D-and L-ritalinic acid were measured in 2-month old mice (equivalent to young adulthood in humans) following a single oral administration of a racemic mixture. Our data show that oral administration of 0.75 mg/kg dose produced within 15 min, plasma levels of D-methylphenidate that correspond to the clinically effective plasma levels in human subjects (estimated to be 6-10 ng/ml). Brain concentrations of Dand L-methylphenidate tended to exceed their plasma concentrations, while the plasma concentrations of D-and L-ritalinic acid exceeded their brain concentrations. A single oral administration at 0.75 mg/kg dose increased dopamine content of the frontal cortex within 1 hr, without producing statistically significant changes in serotonin or noradrenaline contents. Striatal monoamine levels remained unaltered. These data highlight disparities between plasma and brain concentrations of methylphenidate and its metabolites following oral administration and illustrate brain region-and monoamine-specific changes produced by the low oral dose of methylphenidate.

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Section: Discussionmentioning

confidence: 98%

Plasma and brain concentrations of oral therapeutic doses of methylphenidate and their impact on brain monoamine content in mice

et al. 2009

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“…This finding is consistent with that of extensive enantiospecific pharmacokinetic studies that have measured both isomers and found the l-isomer to generally attain only a small fraction of that of circulating concentrations of d-MPH (Table 1). [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] In addition, the plasma half-life (t 1/2 ) of d-MPH is markedly longer than that of l-MPH. 22 The presystemic metabolism and clearance of d,l-MPH is an enantioselective process resulting in markedly higher plasma concentrations of d-MPH relative to l-MPH.…”

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confidence: 99%

Differential Pharmacokinetics and Pharmacodynamics of Methylphenidate Enantiomers

Markowitz¹,

Patrick²

2008

Journal of Clinical Psychopharmacology

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d,l-threo-methylphenidate (MPH) is an effective first-line treatment for the symptoms associated with attention-deficit/hyperactivity disorder. threo-methylphenidate inhibits the dopamine transporter and the norepinephrine transporter, resulting in elevations of these monoamines after impulse release. Although MPH has long been administered as a racemic mixture of the 2 enantiomers, d-MPH and l-MPH, converging lines of evidence drawn from investigations using in vitro systems, animal models, and humans indicate that it is predominantly, if not exclusively, d-MPH that mediates the pharmacological/therapeutic actions of MPH. In both rodent and primate animal models, the binding of radiolabeled d-MPH to dopamine transporter was found to be selective, saturable, and reversible, whereas binding of l-MPH was diffuse and nonspecific. The behavioral effects of the enantiomers of MPH have been tested in several animal models, and results indicate these observed behavioral changes are likewise mediated by d-MPH, whereas l-MPH has little or no effect.The contribution of the l-isomer to the overall pharmacological profile of the racemate remains unclear, owing to several studies suggesting that l-MPH may not be merely an inert isomeric ballast. For example, behavioral studies conducted in rats demonstrate an attenuation of the effect of d-MPH in animals pretreated with l-MPH, suggesting that l-MPH may interfere with the action of the active enantiomer. The importance of MPH chirality to central nervous system MPH receptor targeting has culminated in human imaging studies revealing that d-MPH binds specifically to striatal structures, whereas l-MPH binding is nonspecific. Taken together, data from in vitro, animal, and human studies support the premise that the d-enantiomer of MPH mediates the neurophysiological actions of MPH and therefore likely mediates its clinical efficacy.

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“…[2][3][4] In these studies, determination of both MP and RA required parallel sample processing using liquid-liquid extraction procedures 2,3 or solid phase extraction (SPE) methods that performed well for MP, but gave low recoveries of RA.…”

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Analysis of methylphenidate and its metabolite ritalinic acid in monkey plasma by liquid chromatography/electrospray ionization mass spectrometry

Doerge

Fogle

Paule

et al. 2000

Rapid Commun. Mass Spectrom.

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Methylphenidate (MP, Ritalin) is a psychotropic drug widely prescribed to children for treating the symptoms of attention deficit disorder with and without hyperactivity. Because little information exists about the effects of chronic MP administration on cognitive function in children, measures of behavior changes in non-human primates are important surrogates. An essential component of such studies is the determination of MP plasma levels under chronic and acute dosing conditions. An analytical method was developed that provided sufficient sensitivity to measure low levels of the active parent drug (lower limit of quantitation = 0.25 ng/mL) and the inactive metabolite, ritalinic acid (RA), in monkey plasma as well as the ability to conveniently analyze large numbers of samples. The method uses a polymeric reversed-phase sorbent for solid phase extraction, an efficient reverse-phase high performance liquid chromatography (HPLC) separation, deuterated internal standards for isotope dilution quantification of MP and RA, and detection by sensitive electrospray ionization mass spectrometry (ES-MS) with a single quadrupole instrument. The method responses are linear over the range of plasma concentrations of MP and RA observed in monkeys, gives respective analyte recoveries of 75 and 60% with reasonable precision and accuracy, and demonstrates robust MS performance for rapid determination of MP/RA plasma levels. The average peak MP concentration (ca. 16 ng/mL) and half-lives for MP and RA elimination in monkeys (1.79 and 2.31 h, respectively) were not significantly different under acute vs. chronic dosing conditions and were comparable to values previously reported from human studies.

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Kinetic Analysis of Enantiomers of Threo-Methylphenidate and Its Metabolite in Two Healthy Subjects after Oral Administration as Determined by a Gas Chromatographic-Mass Spectrometric Method

Cited by 48 publications

References 6 publications

Plasma and brain concentrations of oral therapeutic doses of methylphenidate and their impact on brain monoamine content in mice

Plasma and brain concentrations of oral therapeutic doses of methylphenidate and their impact on brain monoamine content in mice

Differential Pharmacokinetics and Pharmacodynamics of Methylphenidate Enantiomers

Analysis of methylphenidate and its metabolite ritalinic acid in monkey plasma by liquid chromatography/electrospray ionization mass spectrometry

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