Brian kinetics of methylphenidate (Ritalin) enantiomers after oral adminstration

Chemistry Department, Brookhaven National Laboratory, Upton, New York 11973-5000, USA.
Synapse (Impact Factor: 2.43). 09/2004; 53(3):168-75. DOI: 10.1002/syn.20046
Source: PubMed

ABSTRACT Methylphenidate (MP) (Ritalin) is widely used for the treatment of attention deficit hyperactivity disorder (ADHD). It is a chiral drug, marketed as the racemic mixture of d- and l-threo enantiomers. Our previous studies (PET and microdialysis) in humans, baboons, and rats confirm the notion that pharmacological specificity of MP resides predominantly in the d-isomer. A recent report that intraperitoneally (i.p.) administered l-threo-MP displayed potent, dose-dependent inhibition of cocaine- or apomorphine-induced locomotion in rats, raises the question of whether l-threo-MP has a similar effect when given orally. It has been speculated that l-threo-MP is poorly absorbed in humans when it is given orally because of rapid presystemic metabolism. To investigate whether l-threo-MP or its metabolites can be delivered to the brain when it is given orally, and whether l-threo-MP is pharmacologically active. PET and MicroPET studies were carried out in baboons and rats using orally delivered C-11-labeled d- and l-threo-MP ([methyl-(11)C]d-threo-MP and [methyl-(11)C]l-threo-MP). In addition, we assessed the effects of i.p. l-threo-MP on spontaneous and cocaine-stimulated locomotor activity in mice. There was a higher global uptake of carbon-11 in both baboon and rat brain for oral [(11)C]l-threo-MP than for oral [(11)C]d-threo-MP. Analysis of the chemical form of radioactivity in rat brain after [(11)C]d-threo-MP indicated mainly unchanged tracer, whereas with [(11)C]l-threo-MP, it was mainly a labeled metabolite. The possibility that this labeled metabolite might be [(11)C]methanol or [(11)C]CO(2), derived from demethylation, was excluded by ex vivo studies in rats. When l-threo-MP was given i.p. to mice at a dose of 3 mg/kg, it neither stimulated locomotor activity nor inhibited the increased locomotor activity due to cocaine administration. These results suggest that, in animal models, l-threo-MP or its metabolite(s) is (are) absorbed from the gastrointestinal tract and enters the brain after oral administration, but that l-threo-MP may not be pharmacologically active. These results are pertinent to the question of whether l-threo-MP contributes to the behavioral and side effect profile of MP during treatment of ADHD.

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Available from: Youwen Xu, Aug 26, 2015
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    • "Previous studies examining the pharmacokinetics of methylphenidate in rodent models also showed that brain concentrations of the compound were consistently higher than plasma concentrations (Patrick et al., 1984; Thai et al., 1999) and that similar to our results, maximal plasma and brain concentrations of D-methylphenidate were attained within 10 min of administration (Thai et al., 1999). A positron emission tomography study using orally administered radiolabeled D-and L-methylphenidate also found higher levels of Lmethylphenidate in the brains of baboons and rats (Ding et al., 2004). Our finding of 4-8 fold difference between brain and plasma concentration of D-methylphenidate at 15 and 30 min following 0.75mg/kg methylphenidate administration tend to agree with findings from earlier studies using intraperitoneal (37μM/kg) or oral (1 mg/kg) administration (Kotaki et al., 1988; Patrick et al., 1984; Thai et al., 1999). "
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    ABSTRACT: Methylphenidate 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 d- and 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 h, 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.
    Neuropharmacology 08/2009; 57(7-8):687-93. DOI:10.1016/j.neuropharm.2009.07.025 · 4.82 Impact Factor
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    • "First, most animal studies using methylphenidate use an i.p. application rather than an oral treatment. Due to differences in the bioavailability of i.p. and orally administered methylphenidate (Ding et al., 2004; Faraj et al., 1974) it is assumed that methylphenidate exerts different effects on the dopaminergic system depending on the method of application. The dose used for oral methylphenidate application in our study was based on the faster hepatic drug metabolism of the gerbil and reflects a clinically relevant dose comparable to the therapeutical dose used in children with ADHD (Grund et al., 2007; cf. "
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    ABSTRACT: Methylphenidate (e.g. Ritalin) is the most common drug used in the treatment of attention-deficit hyperactivity disorder. However, only a few studies have investigated the neuroanatomical long-term effects of this treatment. Prolonged application of methylphenidate during adolescence causes alterations in dopaminergic fiber or receptor densities in adult rodents. This study was conducted to investigate the effects of adolescent methylphenidate treatment on adult hippocampal neurogenesis in male gerbils (Meriones unguiculatus). Animals were first treated with either a single methamphetamine challenge on postnatal day 14 (to cause a disturbance in the dopaminergic system, to mimic the disturbed dopaminergic system seen in ADHD children) or saline and then received a daily oral application of 5 mg/kg methylphenidate or water from postnatal day 30-60 or were left undisturbed. On postnatal 90 gerbils were injected with bromodeoxyuridine (BrdU, a DNA synthesis marker) and sacrificed seven days later. Results reveal that the pretreatment with methamphetamine causes a decrease in the number of BrdU-positive cells in the dentate gyrus. Methylphenidate treatment however did not cause any differences in the number of labelled cells in any group. This implies that, despite methylphenidate's efficiency in inducing changes in the dopaminergic system and associated areas, it might be less effective in altering neurogenesis in the hippocampus.
    European journal of pharmacology 07/2009; 616(1-3):86-90. DOI:10.1016/j.ejphar.2009.06.006 · 2.68 Impact Factor
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    • "In rodents, l-MPH has been reported to increase the behavioral response to cocaine (Ding et al., 2002), though these results were subsequently amended (Ding et al. 2004). It is noted that chromatographic evidence has tentatively supported the hypothesis that oral l-MPH, at least in baboons and rats, accumulates in the brain as the p-hydroxy-MPH metabolite (Ding et al., 2004; see Patrick et al., 1981) with unknown pharmacological implications. Davids et al. (2002) assessed the activity of the separate MPH enantiomers in a 6- hydroxydopamine model of ADHD using rats. "
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    ABSTRACT: The following comprehensive review describes the evolution of stimulant drug formulations used in the treatment of attention-deficit/hyperactivity disorder (ADHD). Emphasis is placed on the basic and clinical pharmacology of the dl-methylphenidate (MPH) transdermal system (MTS). The pharmacokinetic and pharmacodynamic literature pertaining to MPH and amphetamine enantiomers was reviewed in the context of ADHD therapy and MTS as a treatment option. MTS incorporates MPH into an adhesive monolithic matrix, using the free base form of the drug to facilitate transdermal absorption. MTS technology minimizes contact dermatitis by eliminating to need for percutaneous penetration enhancers. After a lag time of approximately 2 h, plasma concentrations of the therapeutic d-MPH isomer become detectable, then continuously rise over the course of the recommended 9 h wear time. Concentrations of l-MPH typically attain 40-50% that of d-MPH (vs. 1-2% following oral MPH). Unauthorized MTS removal poses some misuse liability and over 50% of MTS drug content remains in the discarded system. While liquid or chewable MPH formulations overcome potential swallowing difficulties, as do sprinkled once-daily extended-release (ER) MPH products, only MTS addresses swallowing difficulties while also offering a flexible individualized MPH exposure time in a once-daily MPH regimen.
    Human Psychopharmacology Clinical and Experimental 01/2009; 24(1):1-17. DOI:10.1002/hup.992 · 1.85 Impact Factor
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